159 results on '"Riccardi, Carlo"'
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2. Role of histamine H 4 receptor in the anti-inflammatory pathway of glucocorticoid-induced leucin zipper (GILZ) in a model of lung fibrosis.
- Author
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Sgambellone S, Febo M, Durante M, Marri S, Villano S, Bereshchenko O, Migliorati G, Masini E, Riccardi C, Bruscoli S, and Lucarini L
- Subjects
- Mice, Animals, Histamine, Transcription Factors metabolism, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Receptors, Histamine, Transforming Growth Factor beta metabolism, Glucocorticoids, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis metabolism
- Abstract
Introduction: This study investigates the interactions between histaminergic system and glucocorticoid-induced leucin zipper (GILZ) in the inflammatory process and glucocorticoid modulation in lung fibrosis., Methods: Wild-type (WT) and GILZ Knock-Out (KO) mice were treated with bleomycin (0.05 IU) or saline, delivered by intra-tracheal injection. After surgery, mice received a continuous infusion of JNJ7777120 (JNJ, 2 mg/kg b.wt.) or vehicle for 21 days. Lung function was studied by measuring airway resistance to air insufflation through the analysis of pressure at airway opening (PAO). Lung samples were collected to evaluate the expression of histamine H
4 R, Anx-A1, and p65-NF-kB, the activity of myeloperoxidase (MPO), and the production of pro-inflammatory cytokines., Results: Airway fibrosis and remodeling were assessed by measuring TGF-β production and α-SMA deposition. JNJ reduces PAO in WT but not in GILZ KO mice (from 22 ± 1 mm to 15 ± 0.5 and from 24 ± 1.5 to 19 ± 0.5 respectively), MPO activity (from 204 ± 3.13 pmol/mg to 73.88 ± 2.63 in WT and from 221 ± 4.46 pmol/mg to 107 ± 5.54 in GILZ KO), the inflammatory response, TGF-β production, and α-SMA deposition in comparison to WT and GILZ KO vehicle groups., Conclusion: In conclusion, the role of H4 R and GILZ in relation to glucocorticoids could pave the way for innovative therapies to counteract pulmonary fibrosis., (© 2023. The Author(s).)- Published
- 2023
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3. Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs).
- Author
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Paglialunga M, Flamini S, Contini R, Febo M, Ricci E, Ronchetti S, Bereshchenko O, Migliorati G, Riccardi C, and Bruscoli S
- Abstract
Glucocorticoids (GCs) are commonly used to treat autoimmune and inflammatory diseases, but their clinical effects and long-term use can lead to serious side effects. New drugs that can replace GCs are needed. Glucocorticoid-induced leucine zipper (GILZ) is induced by GCs and mediates many of their anti-inflammatory effects, such as inhibiting the pro-inflammatory molecule NF-κB. The GILZ C-terminal domain (PER region) is responsible for GILZ/p65NF-κB interaction and consequent inhibition of its transcriptional activity. A set of five short peptides spanning different parts of the PER region of GILZ protein was designed, and their anti-inflammatory activity was tested, both in vitro and in vivo. We tested the biological activity of GILZ peptides in human lymphocytic and monocytic cell lines to evaluate their inhibitory effect on the NF-κB-dependent expression of pro-inflammatory cytokines. Among the tested peptides, the peptide named PEP-1 demonstrated the highest efficacy in inhibiting cell activation in vitro. Subsequently, PEP-1 was further evaluated in two in vivo experimental colitis models (chemically induced by DNBS administration and spontaneous colitis induced in IL-10 knock-out (KO) mice (to assess its effectiveness in counteracting inflammation. Results show that PEP-1 reduced disease severity in both colitis models associated with reduced NF-κB pro-inflammatory activity in colon lamina propria lymphocytes. This study explored GILZ-based 'small peptides' potential efficacy in decreasing lymphocyte activation and inflammation associated with experimental inflammatory bowel diseases (IBDs). Small peptides have several advantages over the entire protein, including higher selectivity, better stability, and bioavailability profile, and are easy to synthesize and cost-effective. Thus, identifying active GILZ peptides could represent a new class of drugs for treating IBD patients.
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- 2023
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4. GILZ Modulates the Recruitment of Monocytes/Macrophages Endowed with a Resolving Phenotype and Favors Resolution of Escherichia coli Infection.
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Grossi LC, Zaidan I, Souza JAM, Carvalho AFS, Sanches RCO, Cardoso C, Lara ES, Montuori-Andrade ACM, Bruscoli S, Marchetti MC, Riccardi C, Teixeira MM, Tavares LP, Vago JP, and Sousa LP
- Subjects
- Animals, Mice, Escherichia coli metabolism, Inflammation metabolism, Macrophages metabolism, Monocytes metabolism, Escherichia coli Infections metabolism, Peritonitis metabolism, Transcription Factors metabolism
- Abstract
Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and Escherichia coli- evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-β levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of E. coli -induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ
-/- ) when compared to WT. In addition, GILZ-/- showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of E. coli- evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by E. coli .- Published
- 2023
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5. Immune correlates of protection by vaccine against SARS-CoV-2 in patients with chronic lymphocytic leukaemia.
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Sorcini D, De Falco F, Gargaro M, Bozza S, Guarente V, Cardinali V, Stella A, Adamo FM, Silva Barcelos EC, Rompietti C, Dorillo E, Geraci C, Esposito A, Arcaleni R, Capoccia S, Mameli MG, Graziani A, Moretti L, Cipiciani A, Riccardi C, Mencacci A, Fallarino F, Rosati E, and Sportoletti P
- Subjects
- Humans, COVID-19 Vaccines therapeutic use, Tumor Necrosis Factor-alpha, SARS-CoV-2, Seroepidemiologic Studies, Interferon-gamma, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, COVID-19 prevention & control, Antineoplastic Agents therapeutic use, Vaccines
- Abstract
In chronic lymphocytic leukaemia (CLL) the efficacy of SARS-CoV-2 vaccination remains unclear as most studies have focused on humoral responses. Here we comprehensively examined humoral and cellular responses to vaccine in CLL patients. Seroconversion was observed in 55.2% of CLL with lower rate and antibody titres in treated patients. T-cell responses were detected in a significant fraction of patients. CD4
+ and CD8+ frequencies were significantly increased independent of serology with higher levels of CD4+ cells in patients under a Bruton tyrosine kinase (BTK) or a B-cell lymphoma 2 (BCL-2) inhibitor. Vaccination skewed CD8+ cells towards a highly cytotoxic phenotype, more pronounced in seroconverted patients. A high proportion of patients showed spike-specific CD4+ and CD8+ cells producing interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). Patients under a BTK inhibitor showed increased production of IFNγ and TNFα by CD4+ cells. Vaccination induced a Th1 polarization reverting the Th2 CLL T-cell profile in the majority of patients with lower IL-4 production in untreated and BTK-inhibitor-treated patients. Such robust T-cell responses may have contributed to remarkable protection against hospitalization and death in a cohort of 540 patients. Combining T-cell metrics with seroprevalence may yield a more accurate measure of population immunity in CLL, providing consequential insights for public health., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2023
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6. Association of GILZ with MUC2, TLR2, and TLR4 in Inflammatory Bowel Disease.
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Cari L, Rosati L, Leoncini G, Lusenti E, Gentili M, Nocentini G, Riccardi C, Migliorati G, and Ronchetti S
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- Humans, Mucin-2 genetics, Toll-Like Receptor 2 genetics, Toll-Like Receptor 4 genetics, Colitis, Ulcerative genetics, Colitis, Ulcerative metabolism, Crohn Disease genetics, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases metabolism
- Abstract
Ulcerative colitis (UC) and Crohn's Disease (CD) are chronic relapsing inflammatory diseases that are caused by genetic, environmental, and immune factors. Treatment strategies are currently based on symptomatic control by immunosuppression. The glucocorticoid-induced leucine zipper (GILZ), a mediator of several effects of glucocorticoids, was recently found to be secreted by goblet cells and play a role in inflammatory bowel disease (IBD). This study investigates which genes GILZ is associated with in its role in intestinal barrier functions. We examined datasets from the Gene Expression Omnibus (GEO) and ArrayExpress profiles of the gut of healthy subjects (HSs), as well as UC and CD patients. The human colonic epithelial HT29 cell line was used for in vitro validation experiments. GILZ was significantly correlated with MUC2 , TLR2 , and TLR4 . In particular, an inverse correlation was found between the GILZ and MUC2 in HS and patients with IBD, mostly in those with an active disease. Further, direct pairwise correlations for GILZ / TLR2 and GILZ / TLR4 were found in HSs and UC patients, but not in CD patients. Overall, our results reveal the crosstalk at the transcription level between the GILZ , MUC2 , and TLRs in the mucosal barrier through common pathways, and they open up new perspectives in terms of mucosal healing in IBD patients.
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- 2023
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7. Glucocorticoids and COVID-19.
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Bruscoli S, Puzzovio PG, Zaimi M, Tiligada K, Levi-Schaffer F, and Riccardi C
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- Humans, Glucocorticoids therapeutic use, Glucocorticoids pharmacology, Anti-Inflammatory Agents adverse effects, Autoimmune Diseases drug therapy, COVID-19 Drug Treatment
- Abstract
Coronavirus Disease 19 (COVID-19) is associated with high morbidity and mortality rates globally, representing the greatest health and economic challenge today. Several drugs are currently approved for the treatment of COVID-19. Among these, glucocorticoids (GCs) have received particular attention due to their anti-inflammatory and immunosuppressive effects. In fact, GC are widely used in current clinical practice to treat inflammatory, allergic and autoimmune diseases. Major mechanisms of GC action include inhibition of innate and adaptive immune activity. In particular, an important role is played by the inhibition of pro-inflammatory cytokines and chemokines, and the induction of proteins with anti-inflammatory activity. Overall, as indicated by various national and international regulatory agencies, GCs are recommended for the treatment of COVID-19 in patients requiring oxygen therapy, with or without mechanical ventilation. Regarding the use of GCs for the COVID-19 treatment of non-hospitalized patients at an early stage of the disease, many controversial studies have been reported and regulatory agencies have not recommended their use. The decision to start GC therapy should be based not only on the severity of COVID-19 disease, but also on careful considerations of the benefit/risk profile in individual patients, including monitoring of adverse events. In this review we summarize the effects of GCs on the major cellular and molecular components of the inflammatory/immune system, the benefits and the adverse common reactions in the treatment of inflammatory/autoimmune diseases, as well as in the management of COVID-19., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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8. The novel role of glucocorticoid-induced leucine zipper as a marker of mucosal healing in inflammatory bowel diseases.
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Leoncini G, Gentili M, Lusenti E, Caruso L, Calafà C, Migliorati G, Riccardi C, Villanacci V, and Ronchetti S
- Subjects
- Biomarkers, Humans, Inflammation, Leucine Zippers, Mucous Membrane, Retrospective Studies, Transcription Factors metabolism, Glucocorticoids pharmacology, Inflammatory Bowel Diseases drug therapy
- Abstract
Glucocorticoid-induced leucin zipper (GILZ) mediates the effects of glucocorticoids in immune cells, but little is known about its role in both the gastro-intestinal (GI) mucosa and inflammatory bowel diseases (IBD) in humans. To investigate the GILZ protein expression profile in the GI tract, mucosal biopsies from 80 patients were retrospectively enrolled in this study and subdivided into three groups: 1) patients without clinical-endoscopic and histological evidence of IBD; 2) IBD patients; 3) patients with chronic atrophic gastritis (CAG) and Barrett esophagus (BE), both characterized by intestinal metaplasia (IM). GILZ expression was assessed by immunohistochemical and immunofluorescence methods. Our results showed that GILZ protein was strongly expressed in the secretory cells in healthy mucosa. GILZ expression was reduced in goblet cells in active disease, whereas it was restored in quiescent diseases. Conversely, entero-endocrine cells were not involved in such inflammation-driven dynamics, as GILZ expression remained detectable in active disease. Moreover, GILZ was expressed in IM, but was limited to CAG, and was not detected in BE. In summary, GILZ acts as a secretory protein in the GI mucosa in healthy, hyperplastic and metaplastic conditions. Its secretion by goblet cells is mostly affected by neutrophils mucosal infiltration and seems to be directly related to active mucosal inflammation in IBD. Overall, our findings suggest that GILZ is a suitable molecule to be considered as a histological marker of mucosal healing., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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9. Glucocorticoid-Induced Leucine Zipper Alleviates Lung Inflammation and Enhances Bacterial Clearance during Pneumococcal Pneumonia.
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Souza JAM, Carvalho AFS, Grossi LC, Zaidan I, de Oliveira LC, Vago JP, Cardoso C, Machado MG, Souza GVS, Queiroz-Junior CM, Morand EF, Bruscoli S, Riccardi C, Teixeira MM, Tavares LP, and Sousa LP
- Subjects
- Animals, Glucocorticoids pharmacology, Inflammation metabolism, Leucine Zippers, Mice, Streptococcus pneumoniae metabolism, Transcription Factors metabolism, Pneumonia, Pneumococcal complications, Pneumonia, Pneumococcal drug therapy
- Abstract
Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and proresolving bioactions, yet the therapeutical role of GILZ in infectious diseases remains unexplored. Herein, we investigate the role and effects of GILZ during acute lung injury (ALI) induced by LPS and Streptococcus pneumoniae infection. GILZ deficient mice (GILZ
-/- ) presented more severe ALI, characterized by increased inflammation, decreased macrophage efferocytosis and pronounced lung damage. In contrast, pulmonary inflammation, and damage were attenuated in WT mice treated with TAT-GILZ fusion protein. During pneumococcal pneumonia, TAT-GILZ reduced neutrophilic inflammation and prevented the associated lung damage. There was also enhanced macrophage efferocytosis and bacterial clearance in TAT-GILZ-treated mice. Mechanistically, TAT-GILZ enhanced macrophage phagocytosis of pneumococcus, which was lower in GILZ-/- macrophages. Noteworthy, early treatment with TAT-GILZ rescued 30% of S. pneumoniae -infected mice from lethal pneumonia. Altogether, we present evidence that TAT-GILZ enhances host resilience and resistance to pneumococcal pneumonia by controlling pulmonary inflammation and bacterial loads leading to decreased lethality. Exploiting GILZ pathways holds promise for the treatment of severe respiratory infections.- Published
- 2022
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10. GILZ as a Regulator of Cell Fate and Inflammation.
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Bruscoli S, Riccardi C, and Ronchetti S
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- Animals, Cell Differentiation, Glucocorticoids pharmacology, Humans, Mice, Signal Transduction, Glucocorticoids therapeutic use, Inflammation metabolism, Transcription Factors metabolism
- Abstract
One of the human body's initial responses to stress is the adrenal response, involving the release of mediators that include adrenaline and glucocorticoids (GC). GC are involved in controlling the inflammatory and immune response mechanisms. Of these, the molecular mechanisms that contribute to anti-inflammatory effects warrant more investigation. Previously, we found that GC induced GILZ (glucocorticoid-induced leucine zipper) quickly and widely in thymocytes, T lymphocytes, and other leukocytes. GILZ regulates the activation of cells and is an essential mediator of endogenous GC and the majority of GC anti-inflammatory effects. Further research in this regard could lead to the development of an anti-inflammatory treatment that yields the therapeutic outcomes of GC but without their characteristic adverse effects. Here, we examine the mechanisms of GILZ in the context of GC. Specifically, we review its role in the proliferation and differentiation of cells and in apoptosis. We also examine its involvement in immune cells (macrophages, neutrophils, dendritic cells, T and B lymphocytes), and in non-immune cells, including cancer cells. In conclusion, GILZ is an anti-inflammatory molecule that could mediate the immunomodulatory activities of GC, with less adverse effects, and could be a target molecule for designing new therapies to treat inflammatory diseases.
- Published
- 2021
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11. A recombinant glucocorticoid-induced leucine zipper protein ameliorates symptoms of dextran sulfate sodium-induced colitis by improving intestinal permeability.
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Gentili M, Hidalgo-Garcia L, Vezza T, Ricci E, Migliorati G, Rodriguez-Nogales A, Riccardi C, Galvez J, and Ronchetti S
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- Animals, Anti-Inflammatory Agents administration & dosage, Antigens, Differentiation, B-Lymphocyte metabolism, Colitis metabolism, Cytokines metabolism, Dexamethasone administration & dosage, Disease Models, Animal, Histocompatibility Antigens Class II metabolism, Intestinal Mucosa drug effects, Male, Mice, Mice, Inbred C57BL, Signal Transduction drug effects, Trans-Activators genetics, Transcription Factors genetics, Treatment Outcome, Up-Regulation drug effects, Zonula Occludens-1 Protein metabolism, Colitis chemically induced, Colitis drug therapy, Dextran Sulfate adverse effects, Intestinal Mucosa metabolism, Permeability drug effects, Recombinant Fusion Proteins administration & dosage, Transcription Factors administration & dosage
- Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders characterized by relapsing intestinal inflammation, but many details of pathogenesis remain to be fully unraveled. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory effects of GCs, the most powerful drugs for IBD treatment, but they cause several unwanted side effects. The fusion protein TAT-GILZ has been successfully used in some pre-clinical models of inflammatory and autoimmune diseases. To test the efficacy of TAT-GILZ for treating dextran sulfate sodium (DSS)-induced colitis and explore its impact on the gut microbiome, colitis was induced by DSS in C57BL/6J mice and treated with TAT-GILZ or dexamethasone. Various hallmarks of colitis were analyzed, including disease activity index, gut permeability, and expression of pro-inflammatory cytokines and tight junction proteins. TAT-GILZ treatment showed a therapeutic effect when administered after the onset of colitis. Its efficacy was associated with improved gut permeability, as evidenced by zonula occludens-1 and CD74 upregulation in inflamed colonic tissue. TAT-GILZ also ameliorated the changes in the gut microbiota induced by the DSS, thus potentially providing an optimal environment for colonization of the mucosa surface by beneficial bacteria. Overall, our results demonstrated for the first time that TAT-GILZ treatment proved effective after disease onset allowing restoration of gut permeability, a key pathogenic feature of colitis. Additionally, TAT-GILZ restored gut dysbiosis, thereby contributing to healing mechanisms. Interestingly, we found unprecedented effects of exogenous GILZ that did not overlap with those of GCs., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2021
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12. Glucocorticoid-Induced Leucine Zipper-Mediated TLR2 Downregulation Accounts for Reduced Neutrophil Activity Following Acute DEX Treatment.
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Ricci E, Roselletti E, Gentili M, Sabbatini S, Perito S, Riccardi C, Migliorati G, Monari C, and Ronchetti S
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- Animals, Dexamethasone administration & dosage, Glucocorticoids pharmacology, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils cytology, Neutrophils metabolism, STAT5 Transcription Factor metabolism, Transcription Factors deficiency, Transcription Factors metabolism, Up-Regulation drug effects, Dexamethasone pharmacology, Down-Regulation drug effects, Neutrophils immunology, Toll-Like Receptor 2 metabolism, Transcription Factors genetics
- Abstract
Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions.
- Published
- 2021
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13. Glucocorticoid-Induced Leucine Zipper (GILZ) in Cardiovascular Health and Disease.
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Cappetta D, Bereshchenko O, Cianflone E, Rossi F, Riccardi C, Torella D, Berrino L, Urbanek K, De Angelis A, and Bruscoli S
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- Humans, Leucine Zippers genetics, Leucine Zippers physiology, Cardiovascular System metabolism, Glucocorticoids metabolism
- Abstract
Glucocorticoids (GCs) are essential in regulating functions and homeostasis in many biological systems and are extensively used to treat a variety of conditions associated with immune/inflammatory processes. GCs are among the most powerful drugs for the treatment of autoimmune and inflammatory diseases, but their long-term usage is limited by severe adverse effects. For this reason, to envision new therapies devoid of typical GC side effects, research has focused on expanding the knowledge of cellular and molecular effects of GCs. GC-induced leucine zipper (GILZ) is a GC-target protein shown to mediate several actions of GCs, including inhibition of the NF-κB and MAPK pathways. GILZ expression is not restricted to immune cells, and it has been shown to play a regulatory role in many organs and tissues, including the cardiovascular system. Research on the role of GILZ on endothelial cells has demonstrated its ability to modulate the inflammatory cascade, resulting in a downregulation of cytokines, chemokines, and cellular adhesion molecules. GILZ also has the capacity to protect myocardial cells, as its deletion makes the heart, after a deleterious stimulus, more susceptible to apoptosis, immune cell infiltration, hypertrophy, and impaired function. Despite these advances, we have only just begun to appreciate the relevance of GILZ in cardiovascular homeostasis and dysfunction. This review summarizes the current understanding of the role of GILZ in modulating biological processes relevant to cardiovascular biology.
- Published
- 2021
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14. Editorial: Defects in Regulation: How, Where and When the Immune System Can Go Wrong.
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Rijkers GT, Riccardi C, and Kroese FGM
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- Animals, Humans, Immune System, Immune System Diseases
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2021
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15. Glucocorticoid Therapy in Inflammatory Bowel Disease: Mechanisms and Clinical Practice.
- Author
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Bruscoli S, Febo M, Riccardi C, and Migliorati G
- Subjects
- Animals, Humans, Glucocorticoids therapeutic use, Inflammatory Bowel Diseases drug therapy
- Abstract
Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn's disease (CD). IBD etiopathology is multifactorial and involves alteration of immune cells and chronic activation of the inflammatory cascade against yet unknown environmental factors that trigger the disease. IBD therapy aims at improving the quality of life and reducing the risk of disease-related complications to avoid the need for surgery. There is no specific cure for IBDs, and the focus of therapy is supportive measures and use of anti-inflammatory and immunosuppressive drugs. Glucocorticoids (GCs) are powerful anti-inflammatory and immunomodulatory agents used to treat many acute and chronic inflammatory diseases. GCs remain basic treatment for moderate-to-severe IBD, but their use is limited by several important adverse drug effects. Topical administration of a second-generation of GCs, such as budesonide and beclomethasone dipropionate (BDP), represents a valid alternative to use of older, systemic GCs. Administration of second-generation GCs shows promisingly high topical activity and less systemic toxicity, but maintenance therapy with these new GCs in IBD patients is associated with multiple adverse effects. In this review, we make a comparative analysis of the efficacy of first-generation and second-generation GCs in IBD treatment. Unraveling GC biology at the molecular level to uncouple their clinical benefits from detrimental effects is important. One approach is to consider new GC mediators, such as glucocorticoid-induced leucine zipper, which may have similar anti-inflammatory properties, but avoids the side effects of GCs. This in-depth analysis can help to improve the development and the clinical outcomes of GC therapies in IBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bruscoli, Febo, Riccardi and Migliorati.)
- Published
- 2021
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16. Erratum. Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr + Treg Cells. Diabetes 2020;69:965-980.
- Author
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Cari L, Montanucci P, Basta G, Petrillo MG, Ricci E, Pescara T, Greco A, Cipriani S, Shimizu J, Migliorati G, Nocentini G, Calafiore R, and Riccardi C
- Published
- 2021
- Full Text
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17. Glucocorticoid-induced leucine zipper regulates liver fibrosis by suppressing CCL2-mediated leukocyte recruitment.
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Flamini S, Sergeev P, Viana de Barros Z, Mello T, Biagioli M, Paglialunga M, Fiorucci C, Prikazchikova T, Pagano S, Gagliardi A, Riccardi C, Zatsepin T, Migliorati G, Bereshchenko O, and Bruscoli S
- Subjects
- Animals, Humans, Leukocytes pathology, Liver Cirrhosis pathology, Male, Mice, Mice, Knockout, Chemokine CCL2 metabolism, Leukocytes metabolism, Liver Cirrhosis metabolism, Transcription Factors metabolism
- Abstract
Liver fibrosis (LF) is a dangerous clinical condition with no available treatment. Inflammation plays a critical role in LF progression. Glucocorticoid-induced leucine zipper (GILZ, encoded in mice by the Tsc22d3 gene) mimics many of the anti-inflammatory effects of glucocorticoids, but its role in LF has not been directly addressed. Here, we found that GILZ deficiency in mice was associated with elevated CCL2 production and pro-inflammatory leukocyte infiltration at the early LF stage, resulting in enhanced LF development. RNA interference-mediated in vivo silencing of the CCL2 receptor CCR2 abolished the increased leukocyte recruitment and the associated hepatic stellate cell activation in the livers of GILZ knockout mice. To highlight the clinical relevance of these findings, we found that TSC22D3 mRNA expression was significantly downregulated and was inversely correlated with that of CCL2 in the liver samples of patients with LF. Altogether, these data demonstrate a protective role of GILZ in LF and uncover the mechanism, which can be targeted therapeutically. Therefore, modulating GILZ expression and its downstream targets represents a novel avenue for pharmacological intervention for treating LF and possibly other liver inflammatory disorders.
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- 2021
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18. A Glance at the Use of Glucocorticoids in Rare Inflammatory and Autoimmune Diseases: Still an Indispensable Pharmacological Tool?
- Author
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Ronchetti S, Ayroldi E, Ricci E, Gentili M, Migliorati G, and Riccardi C
- Subjects
- Animals, Humans, Leucine Zippers drug effects, Autoimmune Diseases drug therapy, Glucocorticoids pharmacology, Inflammation drug therapy
- Abstract
Since their discovery, glucocorticoids (GCs) have been used to treat almost all autoimmune and chronic inflammatory diseases, as well as allergies and some forms of malignancies, because of their immunosuppressive and anti-inflammatory effects. Although GCs provide only symptomatic relief and do not eliminate the cause of the pathology, in the majority of treatments, GCs frequently cannot be replaced by other classes of drugs. Consequently, long-term treatments cause adverse effects that may, in turn, lead to new pathologies that sometimes require the withdrawal of GC therapy. Therefore, thus far, researchers have focused their efforts on molecules that have the same efficacy as that of GCs but cause fewer adverse effects. To this end, some GC-induced proteins, such as glucocorticoid-induced leucine zipper (GILZ), have been used as drugs in mouse models of inflammatory pathologies. In this review, we focus on some important but rare autoimmune and chronic inflammatory diseases for which the biomedical research investment in new therapies is less likely. Additionally, we critically evaluate the possibility of treating such diseases with other drugs, either GC-related or unrelated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ronchetti, Ayroldi, Ricci, Gentili, Migliorati and Riccardi.)
- Published
- 2021
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19. Exploiting the pro-resolving actions of glucocorticoid-induced proteins Annexin A1 and GILZ in infectious diseases.
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Vago JP, Tavares LP, Riccardi C, Teixeira MM, and Sousa LP
- Subjects
- Animals, Bacterial Infections immunology, Bacterial Infections metabolism, Bacterial Infections microbiology, Host-Pathogen Interactions, Humans, Inflammation immunology, Inflammation metabolism, Parasitic Diseases immunology, Parasitic Diseases metabolism, Parasitic Diseases parasitology, Remission Induction, Signal Transduction, Treatment Outcome, Virus Diseases immunology, Virus Diseases metabolism, Virus Diseases virology, Annexin A1 metabolism, Anti-Inflammatory Agents therapeutic use, Bacterial Infections drug therapy, Glucocorticoids therapeutic use, Inflammation drug therapy, Parasitic Diseases drug therapy, Transcription Factors metabolism, Virus Diseases drug therapy
- Abstract
For decades, glucocorticoids (GC) have been used to treat several inflammatory conditions, including chronic and autoimmune diseases, due to their potent anti-inflammatory properties. In the context of infectious diseases, the use of GCs may be effective as adjuvant to antibiotic therapy by controlling excessive inflammatory responses resulting in better outcome in some cases. However, the use of GCs has been associated with a vast number of side effects, including increased probability of immunosuppression and consequent risk of opportunistic infection. Glucocorticoid-induced leucine zipper (GILZ) and Annexin A1 (AnxA1) are GC-induced proteins intrinsically involved with the anti-inflammatory functions of GCs without the associated adverse metabolic effects. Recent studies have shown that these GC-proteins exhibit pro-resolving effects. An essential characteristic of pro-resolving molecules is their ability to coordinate the resolution of inflammation and promote host defense in most experimental models of infection. Although the role of GILZ and AnxA1 in the context of infectious diseases remain to be better explored, herein we provide an overview of the emerging functions of these GC-proteins obtained from pre-clinical models of infectious diseases., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2021
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20. Deficit of glucocorticoid-induced leucine zipper amplifies angiotensin-induced cardiomyocyte hypertrophy and diastolic dysfunction.
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Cappetta D, De Angelis A, Flamini S, Cozzolino A, Bereshchenko O, Ronchetti S, Cianflone E, Gagliardi A, Ricci E, Rafaniello C, Rossi F, Riccardi C, Berrino L, Bruscoli S, and Urbanek K
- Subjects
- Angiotensin II, Animals, Blood Pressure, Capillaries pathology, Cell Death, Extracellular Matrix metabolism, Fibrosis, Hypertrophy, Hypertrophy, Left Ventricular complications, Hypertrophy, Left Ventricular pathology, Hypertrophy, Left Ventricular physiopathology, Inflammation pathology, Mice, Inbred C57BL, Mice, Knockout, Transcription Factors genetics, Transcription Factors metabolism, Mice, Diastole, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Transcription Factors deficiency
- Abstract
Poor prognosis in heart failure and the lack of real breakthrough strategies validate targeting myocardial remodelling and the intracellular signalling involved in this process. So far, there are no effective strategies to counteract hypertrophy, an independent predictor of heart failure progression and death. Glucocorticoid-induced leucine zipper (GILZ) is involved in inflammatory signalling, but its role in cardiac biology is unknown. Using GILZ-knockout (KO) mice and an experimental model of hypertrophy and diastolic dysfunction, we addressed the role of GILZ in adverse myocardial remodelling. Infusion of angiotensin II (Ang II) resulted in myocardial dysfunction, inflammation, apoptosis, fibrosis, capillary rarefaction and hypertrophy. Interestingly, GILZ-KO showed more evident diastolic dysfunction and aggravated hypertrophic response compared with WT after Ang II administration. Both cardiomyocyte and left ventricular hypertrophy were more pronounced in GILZ-KO mice. On the other hand, Ang II-induced inflammatory and fibrotic phenomena, cell death and reduction in microvascular density, remained invariant between the WT and KO groups. The analysis of regulators of hypertrophic response, GATA4 and FoxP3, demonstrated an up-regulation in WT mice infused with Ang II; conversely, such an increase did not occur in GILZ-KO hearts. These data on myocardial response to Ang II in mice lacking GILZ indicate that this protein is a new element that can be mechanistically involved in cardiovascular pathology., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2021
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21. GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity.
- Author
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Sakurai T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Kawabe T, Ndhlovu LC, Riccardi C, Kudo H, Wada M, Nio M, So T, and Ishii N
- Subjects
- Animals, Cells, Cultured, Colitis, Ulcerative genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Glucocorticoid-Induced TNFR-Related Protein genetics, Interleukin-15 metabolism, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Colitis, Ulcerative immunology, Glucocorticoid-Induced TNFR-Related Protein metabolism, Intestinal Mucosa immunology, Killer Cells, Natural immunology
- Abstract
Glucocorticoid-induced TNFR family related gene (GITR) is a member of the TNFR superfamily that is expressed on cells of the immune system. Although the protective and pathogenic roles of GITR in T cell immunity are well characterized, the role of GITR in innate immunity in the intestinal tissues has not been well clarified. In this study, using a dextran sulfate sodium (DSS)-induced colitis model in mice, we found that GITR-deficiency rendered mice more susceptible to acute intestinal inflammation and that a significantly higher number of activated natural killer (NK) cells was accumulated in the colonic lamina propria of Gitr
-/- mice as compared to wild-type mice. Additionally, Rag2-/- Gitr-/- mice, which lack T cells but have NK cells, also displayed more severe colonic inflammation than Rag2-/- mice. In contrast, an anti-GITR agonistic antibody significantly alleviated colitis in Rag2-/- mice. Engagement of GITR inhibited IL-15-mediated activating signaling events in NK cells, which include cell activation and proliferation, and production of cytokines and cytotoxic granules. Taken together, our results provide the first evidence that GITR negatively controls intestinal inflammation through NK cell functions., (© 2020 Federation of American Societies for Experimental Biology.)- Published
- 2020
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22. L-GILZ binds and inhibits nuclear factor κB nuclear translocation in undifferentiated thyroid cancer cells.
- Author
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Marchetti MC, Cannarile L, Ronchetti S, Delfino DV, Riccardi C, and Ayroldi E
- Subjects
- Apoptosis, Cell Proliferation, Enzyme Inhibitors pharmacology, Humans, NF-kappa B genetics, Protein Transport, Proto-Oncogene Mas, Thyroid Carcinoma, Anaplastic genetics, Thyroid Carcinoma, Anaplastic metabolism, Thyroid Neoplasms genetics, Thyroid Neoplasms metabolism, Transcription Factors genetics, Tumor Cells, Cultured, Butadienes pharmacology, NF-kappa B metabolism, Nitriles pharmacology, Protein Interaction Domains and Motifs, Thyroid Carcinoma, Anaplastic pathology, Thyroid Neoplasms pathology, Transcription Factors metabolism
- Abstract
Proto-oncogene mutations and abnormal activation of mitogen-activated protein kinase (MAPK) signalling are recurrently found in thyroid cancers. Some thyroid neoplasms respond to drugs that inhibit MAPK pathway activation. Previously, we showed that pharmacological inhibition of MAPK in thyroid cancer cells inhibits cell proliferation and upregulates L-GILZ (long glucocorticoid-induced leucine zipper), a protein with anti-oncogenic and antiproliferative activity, and that L-GILZ is partially responsible for the antiproliferative activity of MAPK inhibitors. Here, we demonstrate that pharmacological inhibition of MAPK in the anaplastic thyroid cancer cell line CAL-62 upregulated L-GILZ, which bound nuclear factor κB (NF-κB) and inhibited its nuclear translocation. These data demonstrate a unique L-GILZ-mediated molecular mechanism that, by trapping NF-κB in the cytoplasm, contributes to the inhibition of proliferation induced by drugs targeting the MAPK transduction cascade. Enhanced knowledge of the mechanism of action of MAPK pathway-inhibiting drugs may improve their clinical use.
- Published
- 2020
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23. Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans.
- Author
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Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, and Lutgens E
- Subjects
- Animals, Apolipoproteins E genetics, Disease Models, Animal, Glucocorticoids, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Receptors, Tumor Necrosis Factor, Atherosclerosis, Glucocorticoid-Induced TNFR-Related Protein, Plaque, Atherosclerotic
- Abstract
Aims: GITR-a co-stimulatory immune checkpoint protein-is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD)., Methods and Results: GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr-/-Apoe-/- mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr-/-Apoe-/- and Apoe-/- monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr-/-Apoe-/- monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity., Conclusion: Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2020
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24. Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR).
- Author
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Platania CBM, Ronchetti S, Riccardi C, Migliorati G, Marchetti MC, Di Paola L, Lazzara F, Drago F, Salomone S, and Bucolo C
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Antibodies, Monoclonal pharmacology, Binding Sites, CD3 Complex antagonists & inhibitors, CD3 Complex immunology, Gene Expression Regulation, Glucocorticoid-Induced TNFR-Related Protein chemistry, Glucocorticoid-Induced TNFR-Related Protein deficiency, Glucocorticoid-Induced TNFR-Related Protein immunology, High-Throughput Screening Assays, Interleukin-17 genetics, Interleukin-17 immunology, Interleukins genetics, Interleukins immunology, Male, Mice, Mice, Knockout, Minocycline pharmacology, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 immunology, Oxytetracycline pharmacology, Primary Cell Culture, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Spleen cytology, Spleen drug effects, Spleen immunology, T-Lymphocytes cytology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tumor Necrosis Factors immunology, Anti-Inflammatory Agents chemistry, Glucocorticoid-Induced TNFR-Related Protein antagonists & inhibitors, Minocycline chemistry, Oxytetracycline chemistry, Tumor Necrosis Factors chemistry
- Abstract
The tumor necrosis factor (TNF) superfamily (TNFSF) includes about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Receptors of the tumor necrosis factor (TNF) superfamily (TNFSFRs) are pharmacological targets for treatment of inflammatory and autoimmune diseases. Currently, drugs targeting TNFSFR signaling are biological drugs (monoclonal antibodies, decoy receptors) aimed at binding and sequestering TNFSFR ligands. The glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) signaling is involved in a series of inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Our study aimed at repurposing FDA approved small molecules as protein-protein disruptors at the GITR ligand (GITRL) trimer, in order to inhibit the binding of GITRL to its receptor (GITR). A structure based molecular modeling approach was carried out to identify, through high throughput virtual screening, GITRL monomer-monomer disruptors. We used a database of ~8,000 FDA approved drugs, and after virtual screening, we focused on two hit compounds, minocycline and oxytetracycline. These two compounds were tested for their capability to modulate IL-17, IL-21 and RORγT expression in T lymphocytes, isolated from wild-type and GITR knock-out (GITR
-/- ) mice. Minocycline showed immunomodulatory effects specific to GITR activation and could represent a novel pharmacological tool to treat inflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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25. Glucocorticoid-induced leucine zipper modulates macrophage polarization and apoptotic cell clearance.
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Vago JP, Galvão I, Negreiros-Lima GL, Teixeira LCR, Lima KM, Sugimoto MA, Moreira IZ, Jones SA, Lang T, Riccardi C, Teixeira MM, Harris J, Morand EF, and Sousa LP
- Subjects
- Animals, Bone Marrow Cells drug effects, Cell Migration Assays, Leukocyte, Cell Physiological Phenomena drug effects, Gene Expression Regulation drug effects, Inflammation chemically induced, Inflammation pathology, Leukocyte Count, Lipopolysaccharides pharmacology, Macrophages drug effects, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Pleural Cavity cytology, Apoptosis drug effects, Glucocorticoids pharmacology, Transcription Factors drug effects
- Abstract
Macrophages are professional phagocytes that display remarkable plasticity, with a range of phenotypes that can be broadly characterized by the M1/M2 dichotomy. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a protein known to mediate anti-inflammatory and some pro-resolving actions, including as neutrophil apoptosis. However, the role of GILZ in key macrophage function is not well understood. Here, we investigated the role of GILZ on macrophage reprogramming and efferocytosis. Using murine bone-marrow-derived macrophages (BMDMs), we found that GILZ was expressed in naive BMDMs and exhibited increased expression in M2-like macrophages (IL4-differentiated). M1-like macrophages (IFN/LPS-differentiated) from GILZ
-/- mice showed higher expression of the M1 markers CD86, MHC class II, iNOS, IL-6 and TNF-α, associated with increased levels of phosphorylated STAT1 and lower IL-10 levels, compared to M1-differentiated cells from WT mice. There were no changes in the M2 markers CD206 and arginase-1 in macrophages from GILZ-/- mice differentiated with IL-4, compared to cells from WT animals. Treatment of M1-like macrophages with TAT-GILZ, a cell-permeable GILZ fusion protein, decreased the levels of CD86 and MHC class II in M1-like macrophages without modifying CD206 levels in M2-like macrophages. In line with the in vitro data, increased numbers of M1-like macrophages were found into the pleural cavity of GILZ-/- mice after LPS-injection, compared to WT mice. Moreover, efferocytosis was defective in the context of GILZ deficiency, both in vitro and in vivo. Conversely, treatment of LPS-injected mice with TAT-GILZ promoted inflammation resolution, associated with lower numbers of M1-like macrophages and increased efferocytosis. Collectively, these data indicate that GILZ is a regulator of important macrophage functions, contributing to macrophage reprogramming and efferocytosis, both key steps for the resolution of inflammation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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26. Glucocorticoid-Induced Leucine Zipper as a Druggable Target in Inflammatory Bowel Diseases.
- Author
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Ronchetti S, Gentili M, Ricci E, Migliorati G, and Riccardi C
- Subjects
- Drug Discovery, Gastrointestinal Microbiome immunology, Humans, Immune Tolerance drug effects, Inflammation, Anti-Inflammatory Agents pharmacology, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases immunology, Transcription Factors pharmacology
- Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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27. Altered glucocorticoid metabolism represents a feature of macroph-aging.
- Author
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Valbuena Perez JV, Linnenberger R, Dembek A, Bruscoli S, Riccardi C, Schulz MH, Meyer MR, Kiemer AK, and Hoppstädter J
- Subjects
- Age Factors, Animals, Cytokines immunology, Cytokines metabolism, Disease Models, Animal, Inflammation immunology, Inflammation metabolism, Inflammation pathology, Macrophage Activation immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Reactive Oxygen Species metabolism, Glucocorticoids immunology, Glucocorticoids metabolism, Macrophages, Peritoneal immunology, Macrophages, Peritoneal metabolism
- Abstract
The aging process is characterized by a chronic, low-grade inflammatory state, termed "inflammaging." It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging-associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11-dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid-induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph-aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2020
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28. Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr + Treg Cells.
- Author
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Cari L, Montanucci P, Basta G, Petrillo MG, Ricci E, Pescara T, Greco A, Cipriani S, Shimizu J, Migliorati G, Nocentini G, Calafiore R, and Riccardi C
- Subjects
- Animals, Cell Proliferation, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Glucocorticoid-Induced TNFR-Related Protein genetics, Mice, Mice, Inbred NOD, Mice, Knockout, Antibodies, Monoclonal, Cell Encapsulation, Diabetes Mellitus, Type 1 prevention & control, Glucocorticoid-Induced TNFR-Related Protein metabolism, Hybridomas, T-Lymphocytes, Regulatory physiology
- Abstract
As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3
+ Treg-cell expansion in the spleen of wild-type mice but not in Gitr-/- mice. G3C/cps also induced the expansion of nonconventional Cd4+ Cd25-/low Foxp3low Gitrint/high (GITR single-positive [sp]) Tregs. Both Cd4+ Cd25+ Gitrhigh Foxp3+ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases., (© 2020 by the American Diabetes Association.)- Published
- 2020
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29. The glucocorticoid-induced leucine zipper mediates statin-induced muscle damage.
- Author
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Hoppstädter J, Valbuena Perez JV, Linnenberger R, Dahlem C, Legroux TM, Hecksteden A, Tse WKF, Flamini S, Andreas A, Herrmann J, Herr C, Müller R, Meyer T, Bals R, Riccardi C, Bruscoli S, and Kiemer AK
- Subjects
- Animals, Blotting, Western, Cell Line, Cells, Cultured, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Humans, In Situ Hybridization, Lentivirus genetics, Mice, Mice, Inbred C57BL, Muscles drug effects, Polyisoprenyl Phosphates pharmacology, Zebrafish, Glucocorticoids pharmacology, Leucine Zippers physiology, Muscles metabolism, Muscles pathology
- Abstract
Statins, the most prescribed class of drugs for the treatment of hypercholesterolemia, can cause muscle-related adverse effects. It has been shown that the glucocorticoid-induced leucine zipper (GILZ) plays a key role in the anti-myogenic action of dexamethasone. In the present study, we aimed to evaluate the role of GILZ in statin-induced myopathy. Statins induced GILZ expression in C2C12 cells, primary murine myoblasts/myotubes, primary human myoblasts, and in vivo in zebrafish embryos and human quadriceps femoris muscle. Gilz induction was mediated by FOXO3 activation and binding to the Gilz promoter, and could be reversed by the addition of geranylgeranyl, but not farnesyl, pyrophosphate. Atorvastatin decreased Akt phosphorylation and increased cleaved caspase-3 levels in myoblasts. This effect was reversed in myoblasts from GILZ knockout mice. Similarly, myofibers isolated from knockout animals were more resistant toward statin-induced cell death than their wild-type counterparts. Statins also impaired myoblast differentiation, and this effect was accompanied by GILZ induction. The in vivo relevance of our findings was supported by the observation that gilz overexpression in zebrafish embryos led to impaired embryonic muscle development. Taken together, our data point toward GILZ as an essential mediator of the molecular mechanisms leading to statin-induced muscle damage., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2020
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30. Regulation of Innate Lymphoid Cells in Acute Kidney Injury: Crosstalk between Cannabidiol and GILZ.
- Author
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Baban B, Khodadadi H, Vaibhav K, Marchetti C, Riccardi C, and Mozaffari MS
- Subjects
- Acute Kidney Injury immunology, Animals, Cells, Cultured, Cytokines metabolism, Disease Models, Animal, Flow Cytometry, Humans, Immunity, Innate, Lymphocytes immunology, Mice, Mice, Inbred BALB C, Receptor Cross-Talk, Receptor, Cannabinoid, CB2 metabolism, Reperfusion Injury immunology, Th2 Cells immunology, Acute Kidney Injury metabolism, Cannabidiol metabolism, Kidney physiology, Lymphocytes metabolism, Reperfusion Injury metabolism, Transcription Factors metabolism
- Abstract
Innate lymphoid cells (ILCs) have emerged as largely tissue-resident archetypal cells of the immune system. We tested the hypotheses that renal ischemia-reperfusion injury (IRI) is a contributing factor to polarization of ILCs and that glucocorticoid-induced leucine zipper (GILZ) and cannabidiol regulate them in this condition. Mice subjected to unilateral renal IRI were treated with the following agents before restoration of renal blood flow: cannabidiol, DMSO, transactivator of transcription- (TAT-) GILZ, or the TAT peptide. Thereafter, kidney cells were prepared for flow cytometry analyses. Sham kidneys treated with either cannabidiol or TAT-GILZ displayed similar frequencies of each subset of ILCs compared to DMSO or TAT, respectively. Renal IRI increased ILC1s and ILC3s but reduced ILC2s compared to the sham group. Cannabidiol or TAT-GILZ treatment of IRI kidneys reversed this pattern as evidenced by reduced ILC1s and ILC3s but increased ILC2s compared to their DMSO- or TAT-treated counterparts. While TAT-GILZ treatment did not significantly affect cells positive for cannabinoid receptors subtype 2 (CB2+), cannabidiol treatment increased frequency of both CB2+ and GILZ-positive (GILZ+) cells of IRI kidneys. Subsequent studies showed that IRI reduced GILZ+ subsets of ILCs, an effect less marked for ILC2s. Treatment with cannabidiol increased frequencies of each subset of GILZ+ ILCs, but the effect was more marked for ILC2s. Indeed, cannabidiol treatment increased CB2+ GILZ+ ILC2s. Collectively, the results indicate that both cannabidiol and GILZ regulate ILC frequency and phenotype, in acute kidney injury, and that the effects of cannabidiol likely relate to modulation of endogenous GILZ., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Babak Baban et al.)
- Published
- 2020
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31. Molecular mechanisms underlying eicosapentaenoic acid inhibition of HDAC1 and DNMT expression and activity in carcinoma cells.
- Author
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Ceccarelli V, Ronchetti S, Marchetti MC, Calvitti M, Riccardi C, Grignani F, and Vecchini A
- Subjects
- Animals, Cell Line, Tumor, CpG Islands, DNA metabolism, DNA (Cytosine-5-)-Methyltransferase 1 metabolism, Genes, Tumor Suppressor, Histone Deacetylase 1 metabolism, Kruppel-Like Transcription Factors biosynthesis, Kruppel-Like Transcription Factors genetics, Liver Neoplasms, Experimental genetics, Liver Neoplasms, Experimental metabolism, PPAR gamma metabolism, Rats, Antineoplastic Agents pharmacology, DNA (Cytosine-5-)-Methyltransferase 1 antagonists & inhibitors, Eicosapentaenoic Acid pharmacology, Epigenesis, Genetic drug effects, Gene Expression Regulation, Neoplastic drug effects, Histone Deacetylase 1 antagonists & inhibitors
- Abstract
DNA methylation and histone acetylation, the most studied epigenetic changes, drive and maintain cancer phenotypes. DNA methyltransferase (DNMT) dysregulation promoted localized hypermethylation in CpG rich regions while upregulated histone deacetylases (HDAC) deacetylated histone tails. Both changes led to close chromatin conformation, suppressing transcription and silencing tumor suppressor genes. Consequently, HDAC and DNMT inhibitors appeared to reprogram the transcriptional circuit and potentiate anti-tumoral activity. Here, we report that eicosapentaenoic acid (EPA), a fatty acid with anti-cancer properties, inhibited HDAC1 and DNMT expression and activity, thus promoting tumor suppressor gene expression. In hepatocarcinoma cells (HCC) EPA bound and activated PPARγ thus downregulating HDAC1 which sequentially reduced expression of DNMT1, 3A and 3B. At the same time, activated PPARγ physically interacted with DNMT1 and HDAC1 in a CpG island on the Hic-1 gene to assemble PPARγ/DNMT1 and PPARγ/HDAC1 protein complexes, which exited from DNA. When EPA and PPARγ were no longer bound, the protein complexes separated into individual proteins. Consequently, DNMT1 and HDAC1 down-regulation and release from DNA inhibited their activities. Overall, EPA-bound PPARγ induced re-expression of the tumor suppressor gene Hic-1. In the present study PPARγ emerged as a master regulator acting synergistically through diverse targets and ways to reveal the epigenetic action of EPA as an HDAC1 and DNMT1 inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Disclosures All authors disclose any potential conflicts (financial, professional, or personal) that are relevant to the manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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32. Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes.
- Author
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Muscari I, Adorisio S, Liberati AM, Thuy TT, Van Sung T, Cannarile L, Ayroldi E, Riccardi C, and Delfino DV
- Abstract
Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous regulators of thymic apoptosis. Among these, glucocorticoid-induced leucine zipper (GILZ) is strongly upregulated in the thymus. We have previously demonstrated that GILZ decreases Bcl-xL expression, activates caspase-8 and caspase-3, and augments apoptosis in mice thymocytes. To better understand the causal links between glucocorticoids, GILZ, Bcl-xL, caspase-8, and caspase-3, we analyzed the thymocytes of Bcl-xL-overexpressing transgenic mice with or without glucocorticoid stimulation in vitro . Overexpression of Bcl-xL inhibited the glucocorticoid-induced up-regulation of GILZ in murine thymocytes as well as the glucocorticoid-dependent activation of caspase-8 and caspase-3. By contrast, no appreciable change in caspase-9 activation was observed upon Bcl-xL overexpression. Thus, these experiments highlighted a novel thymocyte apoptotic pathway in which Bcl-xL overexpression inhibited the glucocorticoid-induced activation of caspase-8 and caspase-3, but not caspase-9, as well as the accumulation of GILZ protein. These findings, together with our previous results showing that caspase-8 protects GILZ from proteasomal degradation, suggest the presence of a glucocorticoid-induced apoptosis self-amplification loop in which GILZ decreases Bcl-xL expression with a subsequent activation of caspase-8 and caspase-3; caspase-8 activation then enhances the stability and accumulation of GILZ and ensures the unimpeded and irreversible progression of apoptosis. By contrast, inappropriate increases in Bcl-xL levels could have catastrophic effects on thymic apoptosis as it would shut down caspase-8/3 activation, diminish the expression of GILZ, and impair the fine control necessary for thymic generation of a healthy immune repertoire., Competing Interests: The authors declare that the submitted work was not carried out in the presence of any personal, professional or financial relationships that could potentially be construed as a conflict of interest., (© 2020 The Author(s).)
- Published
- 2020
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33. Telomeres Increasingly Develop Aberrant Structures in Aging Humans.
- Author
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Boccardi V, Cari L, Nocentini G, Riccardi C, Cecchetti R, Ruggiero C, Arosio B, Paolisso G, Herbig U, and Mecocci P
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Healthy Volunteers, Humans, In Situ Hybridization, Fluorescence, Leukocytes, Mononuclear, Male, Middle Aged, Polymerase Chain Reaction, Telomere Shortening, Aging pathology, Telomere pathology
- Abstract
Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the "end replication problem," or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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34. Identification of 15 T Cell Restricted Genes Evaluates T Cell Infiltration of Human Healthy Tissues and Cancers and Shows Prognostic and Predictive Potential.
- Author
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Cari L, De Rosa F, Petrillo MG, Migliorati G, Nocentini G, and Riccardi C
- Subjects
- Brain Neoplasms pathology, Drug Resistance, Neoplasm genetics, Humans, Neuroblastoma pathology, Nivolumab pharmacology, T-Lymphocytes physiology, Biomarkers, Tumor genetics, Brain Neoplasms genetics, Cell Movement, Neuroblastoma genetics, T-Lymphocytes metabolism
- Abstract
T cell gene signatures are used to evaluate T cell infiltration of non-lymphoid tissues and cancers in both experimental and clinical settings. However, some genes included in the available T cell signatures are not T cell-restricted. Herein, we propose a new human T cell signature that has been developed via a six-step procedure and comprises 15 T cell restricted genes. We demonstrate the new T cell signature, named signature-H, that differs from other gene signatures since it shows higher sensitivity and better predictivity in the evaluation of T cell infiltration in healthy tissues as well as 32 cancers. Further, results from signature-H are highly concordant with the immunohistochemistry methods currently used for assessing the prognosis of neuroblastoma, as demonstrated by the Kaplan-Meier curves of patients ranked by tumor T cell infiltration. Moreover, T cell infiltration levels calculated using signature-H correlate with the risk groups determined by the staging of the neuroblastoma. Finally, multiparametric analysis of tumor-infiltrating T cells based on signature-H let us favorably predict the response of melanoma to the anti-PD-1 antibody nivolumab. These findings suggest that signature-H evaluates T cell infiltration levels of tissues and may be used as a prognostic tool in the precision medicine perspective after appropriate clinical validation.
- Published
- 2019
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35. Novel Immune Targets in Melanoma-Letter.
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Nocentini G, Cari L, and Riccardi C
- Subjects
- Humans, Immunotherapy, Prevalence, Melanoma
- Published
- 2019
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36. Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines.
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Adorisio S, Fierabracci A, Muscari I, Liberati AM, Cannarile L, Thuy TT, Sung TV, Sohrab H, Hasan CM, Ayroldi E, Riccardi C, Mazid A, and Delfino DV
- Subjects
- Animals, Apoptosis drug effects, Bone Marrow Cells drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Female, Humans, Mice, Inbred C57BL, Naphthoquinones isolation & purification, Antineoplastic Agents pharmacology, Cladosporium, Naphthoquinones pharmacology
- Abstract
Cladosporium species are endophytic fungi that grow on organic matter and are considered food contaminants. The anti-microbial and anti-tumor naphthoquinones fusarubin (FUS) and anhydrofusarubin (AFU) were isolated using column chromatography from a Cladosporium species residing inside Rauwolfia leaves. The impact of FUS and AFU on cell growth was assessed in acute myeloid leukemia (OCI-AML3) and other hematologic tumor cell lines (HL-60, U937, and Jurkat). Treatment with FUS or AFU reduced the number of OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses showed that this effect was accompanied by diverse impairments in cell cycle progression. Specifically, FUS (20 or 10 μg/mL significantly decreased the percentage of cells in S phase and increased the percentage of cells in G2/M phase, whereas AFU increased the percentage of cells in G0/G1 phase (50 and 25 μg/mL) and decreased the percentage of cells in S (50 μg/mL) and G2/M (50 and 25 μg/mL) phases. Both substances significantly increased apoptosis at higher concentrations. The effects of FUS were more potent than those of AFU, with FUS up-regulating p21 expression in a p53-dependent manner, as detected by Western blot analyses, likely the consequence of decreased ERK phosphorylation and increased p38 expression (both of which increase p21 stability). FUS also decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers.
- Published
- 2019
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37. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome.
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Bereshchenko O, Lo Re O, Nikulenkov F, Flamini S, Kotaskova J, Mazza T, Le Pannérer MM, Buschbeck M, Giallongo C, Palumbo G, Li Volti G, Pazienza V, Cervinek L, Riccardi C, Krejci L, Pospisilova S, Stewart AF, and Vinciguerra M
- Subjects
- Animals, Cell Differentiation, Chromosome Deletion, Chromosomes, Human, Pair 5 genetics, Disease Models, Animal, Epigenesis, Genetic, Haploinsufficiency, Hematopoietic Stem Cells chemistry, Humans, Mice, Mutation, RNA Splice Sites, Sequence Analysis, RNA, Anemia, Macrocytic genetics, Down-Regulation, Hematopoietic Stem Cells cytology, Histones genetics, Myelodysplastic Syndromes genetics
- Abstract
Background: Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear., Results: MacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis., Conclusions: Together, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies.
- Published
- 2019
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38. Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation.
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Cannarile L, Delfino DV, Adorisio S, Riccardi C, and Ayroldi E
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- Animals, Cell Differentiation immunology, Humans, Receptors, Glucocorticoid immunology, Transcription, Genetic immunology, Glucocorticoids immunology, Immune Tolerance, Lymphocyte Activation, Signal Transduction immunology, T-Lymphocytes immunology, Transcription Factors immunology
- Abstract
Glucocorticoid-induced leucine zipper (GILZ) is a protein with multiple biological roles that is upregulated by glucocorticoids (GCs) in both immune and non-immune cells. Importantly, GCs are immunosuppressive primarily due to their regulation of cell signaling pathways that are crucial for immune system activity. GILZ, which is transcriptionally induced by the glucocorticoid receptor (GR), mediates part of these immunosuppressive, and anti-inflammatory effects, thereby controlling immune cell proliferation, survival, and differentiation. The primary immune cells targeted by the immunosuppressive activity of GCs are T cells. Importantly, the effects of GCs on T cells are partially mediated by GILZ. In fact, GILZ regulates T-cell activation, and differentiation by binding and inhibiting factors essential for T-cell function. For example, GILZ associates with nuclear factor-κB (NF-κB), c-Fos, and c-Jun and inhibits NF-κB-, and AP-1-dependent transcription. GILZ also binds Raf and Ras, inhibits activation of Ras/Raf downstream targets, including mitogen-activated protein kinase 1 (MAPK1). In addition GILZ inhibits forkhead box O3 (FoxO3) without physical interaction. GILZ also promotes the activity of regulatory T cells (Tregs) by activating transforming growth factor-β (TGF-β) signaling. Ultimately, these actions inhibit T-cell activation and modulate the differentiation of T helper (Th)-1, Th-2, Th-17 cells, thereby mediating the immunosuppressive effects of GCs on T cells. In this mini-review, we discuss how GILZ mediates GC activity on T cells, focusing mainly on the therapeutic potential of this protein as a more targeted anti-inflammatory/immunosuppressive GC therapy.
- Published
- 2019
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39. Artocarpus tonkinensis Protects Mice Against Collagen-Induced Arthritis and Decreases Th17 Cell Function.
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Adorisio S, Fierabracci A, Muscari I, Liberati AM, Calvitti M, Cossignani L, Blasi F, Quan TD, Tam NT, Sung TV, Riccardi C, Thuy TT, and Delfino DV
- Abstract
Artocarpus tonkinensis (Moraceae) is a tree that grows in north Vietnam whose leaf decoction is used as a traditional remedy by the Hmong ethnic group to treat arthritis and backache. Our study evaluated the decoction's efficacy and mechanism of action in DBA/1J mice with collagen-induced arthritis (CIA). Mice treated with the decoction (At) either from the first collagen immunization or after CIA development experienced significantly less joint edema and inflammatory infiltration, whereas CIA-induced cartilage damage could only be prevented by early At treatment. Autoimmune gene expression profiles showed that Th17 cell-associated chemokine CCL20 and cytokines IL-6, IL-17, and IL-22 were strongly downregulated by At. Reduced expression of IL-2 , IL-17 , IL-22 , and FasL in lymph node cells from At-treated mice was further confirmed by real-time PCR. The decoction also inhibited polarization of Th17 cells from CD4
+ splenic T cells according to levels of IL-17 and RORC, a Th17 cell-specific transcription factor. Chromatographic analysis identified At's major component as maesopsin-β-D-glucoside, which could inhibit in vitro differentiation of Th17 cells. The decoction significantly alleviated the signs and symptoms of CIA and inhibited the development and function of Th17 cells, highlighting its potent anti-inflammatory activity.- Published
- 2019
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40. Engineered Alginate Microcapsules for Molecular Therapy Through Biologic Secreting Cells.
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Montanucci P, Cari L, Basta G, Pescara T, Riccardi C, Nocentini G, and Calafiore R
- Subjects
- Animals, Capsules, Cell Line, Cells, Immobilized metabolism, Graft Rejection immunology, Graft Rejection prevention & control, Hybridomas, Immunoglobulin M metabolism, Mice, Inbred C57BL, Peritoneum pathology, Rats, Alginates chemistry, Antibodies, Monoclonal therapeutic use
- Abstract
Continuous delivery of monoclonal antibodies (mAbs) at low concentrations may be helpful in the management of several chronic, especially autoimmune diseases. A possible approach to employ mAbs therapy in vivo , in the absence of in vitro manipulations, could be graft of microcapsules containing mAb-secreting hybridoma cells (HY). Sodium alginate (AG) is a polymeric saccharide that permits simple fabrication of microcapsules that are biocompatible and prevent immune recognition of encapsulated cells, upon graft, by the host's immune system. However, at present, AG-based microcapsules are usually impermeable to large molecules. The aim of this study was to engineer the membrane of AG-based microcapsules, to make it permeable to larger molecular weight classes of mAbs. To this end, we have prepared a new AG-based membrane, using standard reagents already in use, but following different coating procedures and molar ratios. In particular, we fabricated a new capsular membrane permeable to IgM synthesized by the HY cell line, G3C. Morphologic structural and ultrastructural analysis of the new membranes before and after intraperitoneal transplant, in conjunction with IgM outflow secretory kinetics underwent both, in vitro and in vivo assessments. While allowing immunoprotection of the enveloped HY, as demonstrated by the absence of any inflammatory response, the microcapsules permitted G3c mAb egress, on a regulated delivery kinetics. HY viability persisted, upon transplant, for long time periods. In summary, the new AG-based microcapsules allow delivery of big molecules out of the capsules, while protecting the enveloped HY from the host's immune system. These microcapsules could apply to implant cells producing fully active large molecules without the need of time- and cost expensive procedures to purify them.
- Published
- 2019
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41. Glucocorticoid-Induced Leucine Zipper: A Novel Anti-inflammatory Molecule.
- Author
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Bereshchenko O, Migliorati G, Bruscoli S, and Riccardi C
- Abstract
Glucocorticoids (GCs) are the most commonly used drugs for treatment of autoimmune and inflammatory diseases. Their efficacy is due to their ability to bind cytoplasmic receptors (glucocorticoid receptors, GR) and other cytoplasmic proteins, thus regulating gene expression. Although GCs are potent life-saving drugs, their therapeutic effects are transitory and chronic use of GCs is accompanied by serious side effects. Therefore, new drugs are needed to replace GCs. We have identified a gene, glucocorticoid-induced leucine zipper (GILZ or tsc22d3), that is rapidly and invariably induced by GCs. Human GILZ is a 135-amino acid protein that mediates many GC effects, including inhibition of the NF-κB and MAPK pathways. Similar to GCs, GILZ exerts anti-inflammatory activity in experimental disease models, including inflammatory bowel diseases and arthritis. While transgenic mice that overexpress GILZ are more resistant, GILZ knockout mice develop worse inflammatory diseases. Moreover, the anti-inflammatory effect of GCs is attenuated in GILZ-deficient mice. Importantly, in vivo delivery of recombinant GILZ protein cured colitis and facilitated resolution of lipopolysaccharide-induced inflammation without apparent toxic effects. A synthetic GILZ-derived peptide, corresponding to the GILZ region that interacts with NF-κB, was able to suppress experimental autoimmune encephalomyelitis. Collectively, these findings indicate that GILZ is an anti-inflammatory molecule that may serve as the basis for designing new therapeutic approaches to inflammatory diseases.
- Published
- 2019
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42. Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications.
- Author
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Cari L, De Rosa F, Nocentini G, and Riccardi C
- Subjects
- Animals, Cell Differentiation drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Humans, Mice, T-Lymphocytes, Regulatory drug effects, Glucocorticoids pharmacology, T-Lymphocytes, Regulatory cytology
- Abstract
Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment.
- Published
- 2019
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43. Selective CB2 inverse agonist JTE907 drives T cell differentiation towards a Treg cell phenotype and ameliorates inflammation in a mouse model of inflammatory bowel disease.
- Author
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Gentili M, Ronchetti S, Ricci E, Di Paola R, Gugliandolo E, Cuzzocrea S, Bereshchenko O, Migliorati G, and Riccardi C
- Subjects
- Animals, Cell Differentiation, Colitis pathology, Colon drug effects, Colon pathology, Cytokines immunology, Disease Models, Animal, Inflammation immunology, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases pathology, Male, Mice, Inbred C57BL, Phenotype, Spleen cytology, T-Lymphocytes cytology, T-Lymphocytes immunology, Anti-Inflammatory Agents pharmacology, Colitis immunology, Dioxoles pharmacology, Quinolones pharmacology, Receptor, Cannabinoid, CB2 immunology, T-Lymphocytes drug effects
- Abstract
Cannabinoids are known to possess anti-inflammatory and immunomodulatory properties, but the mechanisms involved are not fully understood. CB2 is the cannabinoid receptor that is expressed primarily on hematopoietic cells and mediates the immunoregulatory functions of cannabinoids. In order to study the effect of JTE907, a selective/inverse agonist of CB2 with anti-inflammatory properties, on the differentiation of T cell subtypes, we used an in vitro system of Th lineage-specific differentiation of naïve CD4
+ T lymphocytes isolated from the mouse spleen. The results indicate that JTE907 was able to induce the differentiation of Th0 cells into the Treg cell phenotype, which was characterized by the expression of FoxP3, TGF-β and IL-10. P38 phosphorylation and STAT5A activation were found to mediate the signaling pathway triggered by JTE907 via the CB2 receptor in Th0 lymphocytes. In mice with DNBS-induced colitis, JTE907 treatment was able to induce an increase in the number of CD4+ CD25+ FoxP3+ cells in the lamina propria after 24 h of disease onset and reduce disease severity after 48 h. Further, longer JTE907 treatment resulted in less severe colitis even when administered orally, resulting in less body weight loss, reduction of the disease score, prevention of NF-κB activation, and reduction of the expression of adhesion molecules. Collectively, the results of this study indicate that specific signals delivered through the CB2 receptor can drive the immune response towards the Treg cell phenotype. Thus, ligands such as JTE907 may have use as potential therapeutic agents in autoimmune and inflammatory diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2019
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44. Amplified Host Defense by Toll-Like Receptor-Mediated Downregulation of the Glucocorticoid-Induced Leucine Zipper (GILZ) in Macrophages.
- Author
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Hoppstädter J, Diesel B, Linnenberger R, Hachenthal N, Flamini S, Minet M, Leidinger P, Backes C, Grässer F, Meese E, Bruscoli S, Riccardi C, Huwer H, and Kiemer AK
- Subjects
- Adaptor Proteins, Vesicular Transport metabolism, Animals, Cell Line, Tumor, Down-Regulation genetics, Down-Regulation immunology, Host-Pathogen Interactions drug effects, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Macrophage Activation, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs metabolism, Myeloid Differentiation Factor 88 metabolism, Phagocytosis immunology, Poly I-C pharmacology, Primary Cell Culture, Salmonella Infections microbiology, Salmonella typhimurium immunology, Toll-Like Receptors agonists, Transcription Factors immunology, Transcription Factors metabolism, Up-Regulation drug effects, Up-Regulation genetics, Up-Regulation immunology, Macrophages immunology, Salmonella Infections immunology, Toll-Like Receptors metabolism, Transcription Factors genetics
- Abstract
Activation of toll-like receptors (TLRs) plays a pivotal role in the host defense against bacteria and results in the activation of NF-κB-mediated transcription of proinflammatory mediators. Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory mediator, which inhibits NF-κB activity in macrophages. Thus, we aimed to investigate the regulation and role of GILZ expression in primary human and murine macrophages upon TLR activation. Treatment with TLR agonists, e.g., Pam
3 CSK4 (TLR1/2) or LPS (TLR4) rapidly decreased GILZ mRNA and protein levels. In consequence, GILZ downregulation led to enhanced induction of pro-inflammatory mediators, increased phagocytic activity, and a higher capacity to kill intracellular bacteria ( Salmonella enterica serovar typhimurium ), as shown in GILZ knockout macrophages. Treatment with the TLR3 ligand polyinosinic: polycytidylic acid [Poly(I:C)] did not affect GILZ mRNA levels, although GILZ protein expression was decreased. This effect was paralleled by sensitization toward TLR1/2- and TLR4-agonists. A bioinformatics approach implicated more than 250 miRNAs as potential GILZ regulators. Microarray analysis revealed that the expression of several potentially GILZ-targeting miRNAs was increased after Poly(I:C) treatment in primary human macrophages. We tested the ability of 11 of these miRNAs to target GILZ by luciferase reporter gene assays. Within this small set, four miRNAs (hsa-miR-34b* ,-222,-320d,-484) were confirmed as GILZ regulators, suggesting that GILZ downregulation upon TLR3 activation is a consequence of the synergistic actions of multiple miRNAs. In summary, our data show that GILZ downregulation promotes macrophage activation. GILZ downregulation occurs both via MyD88-dependent and -independent mechanisms and can involve decreased mRNA or protein stability and an attenuated translation.- Published
- 2019
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45. GILZ restrains neutrophil activation by inhibiting the MAPK pathway.
- Author
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Ricci E, Ronchetti S, Gabrielli E, Pericolini E, Gentili M, Roselletti E, Vecchiarelli A, and Riccardi C
- Subjects
- Animals, Candida albicans physiology, Candidiasis complications, Candidiasis immunology, Candidiasis microbiology, Candidiasis pathology, Colitis complications, Colitis immunology, Colitis pathology, Disease Models, Animal, Male, Mice, Inbred C57BL, Mice, Knockout, Neutrophils metabolism, Respiratory Burst, MAP Kinase Signaling System, Neutrophil Activation, Transcription Factors metabolism
- Abstract
Glucocorticoid-induced leucine zipper (GILZ) exerts anti-inflammatory effects on the immune cells. However, less is known about GILZ function in neutrophils. We aimed to define the specific role of GILZ in basal neutrophil activity during an inflammatory response. GILZ knockdown resulted in a persistent activation state of neutrophils, as evidenced by increased phagocytosis, killing activity, and oxidative burst in GILZ-knockout (KO) neutrophils. This enhanced response caused severe disease in a dinitrobenzene sulfonic acid (DNBS)-induced colitis model, where GILZ-KO mice had prominent granulocytic infiltrate and excessive inflammatory state. We used a Candida albicans intraperitoneal infection model to unravel the intracellular pathways affected by GILZ expression in activated neutrophils. GILZ-KO neutrophils had stronger ability to clear the infectious agent than the wild-type (WT) neutrophils, and there was more activation of the NOX2 (NADPH oxidase 2) and p47
phox proteins, which are directly involved in oxidative burst. Similarly, the MAPK pathway components, that is, ERK and p38, which are involved in the oxidative burst pathway, were highly phosphorylated in GILZ-KO neutrophils. Evaluation of GILZ expression kinetics during C. albicans infection revealed down-regulation that correlated inversely with the state of neutrophil activation, which was evaluated as oxidative burst. Overall, our findings define GILZ as a regulator of neutrophil functions, as its expression contributes to limiting neutrophil activation by reducing the activation of the signaling pathways that control the basal neutrophil functions. Controlling GILZ expression could help regulate a continuous inflammatory state that can result in chronic inflammatory and autoimmune diseases., (©2018 Society for Leukocyte Biology.)- Published
- 2019
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46. How Glucocorticoids Affect the Neutrophil Life.
- Author
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Ronchetti S, Ricci E, Migliorati G, Gentili M, and Riccardi C
- Subjects
- Animals, Humans, Inflammation drug therapy, Inflammation immunology, Inflammation pathology, Neutrophils pathology, Anti-Inflammatory Agents immunology, Anti-Inflammatory Agents therapeutic use, Apoptosis drug effects, Apoptosis immunology, Glucocorticoids immunology, Glucocorticoids therapeutic use, Immunity, Innate drug effects, Neutrophils immunology
- Abstract
Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions.
- Published
- 2018
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47. Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury.
- Author
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Baban B, Marchetti C, Khodadadi H, Malik A, Emami G, Lin PC, Arbab AS, Riccardi C, and Mozaffari MS
- Subjects
- Acute Kidney Injury metabolism, Animals, Gene Expression Regulation drug effects, Interleukin-10 metabolism, Interleukin-17 metabolism, Kidney drug effects, Kidney metabolism, Lymphocyte Activation drug effects, Male, Mice, Mice, Inbred BALB C, T-Lymphocytes, Regulatory metabolism, Th17 Cells metabolism, Trans-Activators metabolism, Transcription Factors metabolism, Up-Regulation drug effects, Acute Kidney Injury drug therapy, Glucocorticoids pharmacology, Leucine Zippers drug effects, Neutrophils drug effects, T-Lymphocytes, Regulatory drug effects, Th17 Cells drug effects
- Abstract
The glucocorticoid-induced leucine zipper (GILZ) mediates anti-inflammatory effects of glucocorticoids. Acute kidney injury (AKI) mobilizes immune/inflammatory mechanisms, causing tissue injury, but the impact of GILZ in AKI is not known. Neutrophils play context-specific proinflammatory [type 1 neutrophil (N1)] and anti-inflammatory [type 2 neutrophil (N2)] functional roles. Also, regulatory T lymphocytes (Tregs) and regulatory T-17 (Treg17) cells exert counterinflammatory effects, including the suppression of effector T lymphocytes [e.g., T-helper (Th) 17 cells]. Thus, utilizing cell preparations of mice kidneys subjected to AKI or sham operation, we determined the effects of GILZ on T cells and neutrophil subtypes in the context of its renoprotective effect; these studies used the transactivator of transcription (TAT)-GILZ or the TAT peptide. AKI increased N1 and Th-17 cells but reduced N2, Tregs, and Treg17 cells in association with increased interleukin (IL)-17
+ but reduced IL-10+ cells accompanied with the disruption of mitochondrial membrane potential ( ψm ) and increased apoptosis/necrosis compared with sham kidneys. TAT-GILZ, compared with TAT, treatment reduced N1 and Th-17 cells but increased N2 and Tregs, without affecting Treg17 cells, in association with a reduction in IL-17+ cells but an increase in IL-10+ cells; TAT-GILZ caused less disruption of ψm and reduced cell death in AKI. Importantly, TAT-GILZ increased perfusion of the ischemic-reperfused kidney but reduced tissue edema compared with TAT. Utilizing splenic T cells and bone marrow-derived neutrophils, we further showed marked reduction in the proliferation of Th cells in response to TAT-GILZ compared with response to TAT. Collectively, the results indicate that GILZ exerts renoprotection accompanied by the upregulation of the regulatory/suppressive arm of immunity in AKI, likely via regulating cross talk between T cells and neutrophils., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2018
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48. Role of Endogenous Glucocorticoids in Cancer in the Elderly.
- Author
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Ayroldi E, Cannarile L, Adorisio S, Delfino DV, and Riccardi C
- Subjects
- Age Factors, Aged, Aged, 80 and over, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic metabolism, Genomic Instability, Humans, Immunosenescence genetics, Neoplasms genetics, Neoplasms immunology, Glucocorticoids metabolism, Neoplasms metabolism
- Abstract
Although not a disease itself, aging represents a risk factor for many aging-related illnesses, including cancer. Numerous causes underlie the increased incidence of malignancies in the elderly, for example, genomic instability and epigenetic alterations that occur at cellular level, which also involve the immune cells. The progressive decline of the immune system functions that occurs in aging defines immunosenescence, and includes both innate and adaptive immunity; the latter undergoes major alterations. Aging and chronic stress share the abnormal hypothalamic⁻pituitary⁻adrenal axis activation, where altered peripheral glucocorticoids (GC) levels and chronic stress have been associated with accelerated cellular aging, premature immunosenescence, and aging-related diseases. Consequently, changes in GC levels and sensitivity contribute to the signs of immunosenescence, namely fewer naïve T cells, poor immune response to new antigens, decreased cell-mediated immunity, and thymic involution. GC signaling alterations also involve epigenetic alterations in DNA methylation, with transcription modifications that may contribute to immunosenescence. Immune cell aging leads to decreased levels of immunosurveillance, thereby providing tumor cells one more route for immune system escape. Here, the contribution of GC secretion and signaling dysregulation to the increased incidence of tumorigenesis in the elderly is reviewed.
- Published
- 2018
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49. Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy.
- Author
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Riccardi C, Ronchetti S, and Nocentini G
- Subjects
- Animals, Autoimmune Diseases immunology, Autoimmune Diseases therapy, Disease Models, Animal, Glucocorticoid-Induced TNFR-Related Protein genetics, Glucocorticoid-Induced TNFR-Related Protein immunology, Humans, Inflammation immunology, Inflammation therapy, Mice, Neoplasms immunology, Neoplasms therapy, Species Specificity, Glucocorticoid-Induced TNFR-Related Protein antagonists & inhibitors, Immunotherapy methods, Molecular Targeted Therapy
- Abstract
Introduction: Triggering of the glucocorticoid-induced TNFR-related gene (GITR) increases the activation of T lymphocytes and other immune system cells; furthermore, its ligand, GITRL, delivers signals in the cells where it is expressed. Areas covered: This review describes the effects of GITR/GITRL triggering/inhibition in conventional T cells, regulatory T cells (Tregs), monocytes/macrophages, endothelial cells and other cells of the immune system. GITR triggering appears to be an approach for promoting tumor rejection, treating infection and boosting vaccinations in several murine models. GITR inhibition may be useful for inhibiting inflammation and autoimmune disease development. Expert opinion: The exciting antitumor activity of anti-GITR mAbs depends on CD8
+ effector T cell activation and inhibition/deletion of tumor-infiltrating Tregs. Whether one of these effects is more relevant is still under debate. Inhibition of GITR triggering plays an interesting anti-inflammatory role, but the potential effect of long-term treatment is to be investigated. The use of adjuvants able to trigger GITR is promising regarding new vaccines. Finally, caution is recommended when translating the findings of experimental murine models to human diseases; biologicals modulating human GITR/GITRL system can behave differently from those modulating the murine GITR/GITRL system.- Published
- 2018
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50. Defining the role of glucocorticoids in inflammation.
- Author
-
Ronchetti S, Migliorati G, Bruscoli S, and Riccardi C
- Subjects
- Animals, Anti-Inflammatory Agents adverse effects, Autoimmune Diseases immunology, Glucocorticoids adverse effects, Humans, Hypertension chemically induced, Immune System cytology, Immune System drug effects, Immune System immunology, Inflammation immunology, Osteoporosis chemically induced, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid immunology, Receptors, Glucocorticoid metabolism, Anti-Inflammatory Agents therapeutic use, Autoimmune Diseases drug therapy, Glucocorticoids therapeutic use, Inflammation drug therapy
- Abstract
An established body of knowledge and clinical practice has argued in favor of the use of glucocorticoids in various chronic inflammatory and autoimmune diseases. However, the very well-known adverse effects associated with their treatment hampers continuation of therapy with glucocorticoids. Analyses of the molecular mechanisms underlying the actions of glucocorticoids have led to the discovery of several mediators that add complexity and diversity to the puzzling world of these hormones and anti-inflammatory drugs. Such mediators hold great promise as alternative pharmacologic tools to be used as anti-inflammatory drugs with the same properties as glucocorticoids, but avoiding their metabolic side effects. This review summarizes findings about the molecular targets and mediators of glucocorticoid function., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2018
- Full Text
- View/download PDF
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