62 results on '"Hams, E."'
Search Results
2. Surface functionalization of nanoparticles with di(a,2→8) N-acetylneuraminic acid can ameliorate septic shock through activation of inhibitory Siglec receptors: W56.002
- Author
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Spence, S., Fay, F., Greene, M. K., Schmid, D., Hams, E., Saunders, S. P., and Scott, C.
- Published
- 2012
3. Nuocyte development and function are critical for type-2 immunity: W39.006
- Author
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Barlow, J., Walker, J. A., Wong, S. H., Jolin, H. E., Hams, E., Drynan, L. F., Fallon, P. G., and McKenzie, A. N. M.
- Published
- 2012
4. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis
- Author
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Cooke, G, primary, Kamal, I, additional, Strengert, M, additional, Hams, E, additional, Mawhinney, L, additional, Tynan, A, additional, O’Reilly, C, additional, O’Dwyer, D N, additional, Kunkel, S L, additional, Knaus, U G, additional, Shields, D C, additional, Moller, D R, additional, Bowie, A G, additional, Fallon, P G, additional, Hogaboam, C M, additional, Armstrong, M E, additional, and Donnelly, S C, additional
- Published
- 2017
- Full Text
- View/download PDF
5. P2.02-069 Targeting Neuropilin-1 in NSCLC
- Author
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Barr, M., primary, Pidgeon, G., additional, Gray, S., additional, Gately, K., additional, Hams, E., additional, Fallon, P., additional, Cuffe, S., additional, Finn, S., additional, and O’Byrne, K., additional
- Published
- 2017
- Full Text
- View/download PDF
6. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis.
- Author
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Kunkel, S. L., Cooke, G., Strengert, M., O'Dwyer, D. N., Knaus, U. G., Kamal, I., Hams, E., Mawhinney, L., Tynan, A., O'Reilly, C., Armstrong, M. E., Donnelly, S. C., Fallon, P. G., Shields, D. C., Moller, D. R., Bowie, A. G., and Hogaboam, C. M.
- Subjects
SARCOIDOSIS ,TOLL-like receptors ,GENETIC polymorphisms ,PHENOTYPES ,ETIOLOGY of diseases ,GRANULOMA ,GENETICS - Abstract
Background/Introduction: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. Aim: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. Design: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. Methods: Cohorts of Irish sarcoidosis patients (n=228), healthy Irish controls (n=263) and a secondary cohort of American sarcoidosis patients (n=123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. Results: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 Fhomozygous pulmonary sarcoidosis patients resulted in reduced IFN-β and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. Discussion/Conclusion: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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7. VEGF autocrine survival signalling is mediated via neuropilin 1 receptor in NSCLC cells
- Author
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Barr, M.P., Gray, G., Gately, K.A., Hams, E., Fallon, P.G., Davies, A. Mitchell, Richard, D.J., Pidgeon, G.P., Cuffe, S., Finn, S., O?Byrne, K. J., Barr, M.P., Gray, G., Gately, K.A., Hams, E., Fallon, P.G., Davies, A. Mitchell, Richard, D.J., Pidgeon, G.P., Cuffe, S., Finn, S., and O?Byrne, K. J.
- Published
- 2014
8. 12 VEGF autocrine survival signalling is mediated via neuropilin 1 receptor in NSCLC cells
- Author
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Barr, M.P., primary, Gray, G., additional, Gately, K.A., additional, Hams, E., additional, Fallon, P.G., additional, Davies, A. Mitchell, additional, Richard, D.J., additional, Pidgeon, G.P., additional, Cuffe, S., additional, Finn, S., additional, and O'Byrne, K.J., additional
- Published
- 2014
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9. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from lipopolysaccharide-stimulated myeloid cells
- Author
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Gleeson, E. M., primary, O'Donnell, J. S., additional, Hams, E., additional, Ainle, F. N., additional, Kenny, B.-A., additional, Fallon, P. G., additional, and Preston, R. J. S., additional
- Published
- 2013
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10. Oncostatin M receptor-β signaling limits monocytic cell recruitment in acute inflammation
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Hams, E., Colmont, C. S., Dioszeghy, V., Hammond, V. J., Fielding, C. A., Williams, A. S., Tanaka, M., Miyajima, A., Taylor, P. R., Topley, N., and Simon Arnett Jones
11. The Schistosoma Granuloma: Friend or Foe?
- Author
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Emily Hams, Gabriella Aviello, Padraic G. Fallon, Hams, E., Aviello, G., and Fallon, P. G.
- Subjects
lcsh:Immunologic diseases. Allergy ,Pathology ,medicine.medical_specialty ,Fibrosi ,Immunology ,Cercarial Dermatitis ,Inflammation ,Schistosomiasis ,Review Article ,Biology ,Fibrosis ,medicine ,Immunology and Allergy ,granuloma ,Schistosoma ,fibrosis ,Schistosoma mansoni ,medicine.disease ,biology.organism_classification ,inflammation ,Granuloma ,medicine.symptom ,lcsh:RC581-607 ,Infiltration (medical) - Abstract
Infection of man with Schistosoma species of trematode parasite causes marked chronic morbidity. Individuals that become infected with Schistosomes may develop a spectrum of pathology ranging from mild cercarial dermatitis to severe tissue inflammation, in particular within the liver and intestines, which can lead to life threatening hepatosplenomegaly. It is well established that the etiopathology during schistosomiasis is primarily due to an excessive or unregulated inflammatory response to the parasite, in particular to eggs that become trapped in various tissue. The eggs forms the foci of a classical type 2 granulomatous inflammation, characterized by an eosinophil rich, CD4+ T helper (Th) 2 cell dominated infiltrate with additional infiltration of alternatively activated macrophages (M2). Indeed the sequela of the type 2 perioval granuloma is marked fibroblast infiltration and development of fibrosis. Paradoxically, while the granuloma is the cause of pathology it also can afford some protection, whereby the granuloma minimizes collateral tissue damage in the liver and intestines. Furthermore, the parasite is exquisitely reliant on the host to mount a granulomatous reaction to the eggs as this inflammatory response facilitates the successful excretion of the eggs from the host. In this focused review we will address the conundrum of the S. mansoni granuloma acting as both friend and foe in inflammation during infection.
- Published
- 2013
12. Retinoic Acid-Related Orphan Receptor α Is Required for Generation of Th2 Cells in Type 2 Pulmonary Inflammation.
- Author
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Roberts J, Chevalier A, Hawerkamp HC, Yeow A, Matarazzo L, Schwartz C, Hams E, and Fallon PG
- Subjects
- Mice, Animals, Th2 Cells, Retinoic Acid Receptor alpha, CD4-Positive T-Lymphocytes, Tretinoin, Immunity, Innate, Pneumonia
- Abstract
The transcription factor retinoic acid-related orphan receptor α (RORα) is important in regulating several physiological functions, such as cellular development, circadian rhythm, metabolism, and immunity. In two in vivo animal models of type 2 lung inflammation, Nippostrongylus brasiliensis infection and house dust mite (HDM) sensitization, we show a role for Rora in Th2 cellular development during pulmonary inflammation. N. brasiliensis infection and HDM challenge induced an increase in frequency of Rora-expressing GATA3+CD4 T cells in the lung. Using staggerer mice, which have a ubiquitous deletion of functional RORα, we generated bone marrow chimera mice, and we observed a delayed worm expulsion and reduced frequency in the expansion of Th2 cells and innate lymphoid type 2 cells (ILC2s) in the lungs after N. brasiliensis infection. ILC2-deficient mouse (Rorafl/flIl7raCre) also had delayed worm expulsion with associated reduced frequency of Th2 cells and ILC2s in the lungs after N. brasiliensis infection. To further define the role for Rora-expressing Th2 cells, we used a CD4-specific Rora-deficient mouse (Rorafl/flCD4Cre), with significantly reduced frequency of lung Th2 cells, but not ILC2, after N. brasiliensis infection and HDM challenge. Interestingly, despite the reduction in pulmonary Th2 cells in Rorafl/flCD4Cre mice, this did not impact the expulsion of N. brasiliensis after primary and secondary infection, or the generation of lung inflammation after HDM challenge. This study demonstrates a role for RORα in Th2 cellular development during pulmonary inflammation that could be relevant to the range of inflammatory diseases in which RORα is implicated., (Copyright © 2023 The Authors.)
- Published
- 2023
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13. Discovery and multi-parametric optimization of a high-affinity antibody against interleukin-25 with neutralizing activity in a mouse model of skin inflammation.
- Author
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Bone R, Fennell BJ, Tam A, Sheldon R, Nocka K, Varghese S, Chang CS, Hawerkamp HC, Yeow A, Saunders SP, Hams E, Walsh PT, Cunningham O, and Fallon PG
- Abstract
Background: Interleukin (IL)25 has been implicated in tissue homeostasis at barrier surfaces and the initiation of type two inflammatory signaling in response to infection and cell injury across multiple organs. We sought to discover and engineer a high affinity neutralizing antibody and evaluate the antibody functional activity in vitro and in vivo ., Methods: In this study, we generated a novel anti-IL25 antibody (22C7) and investigated the antibody's therapeutic potential for targeting IL25 in inflammation., Results: A novel anti-IL25 antibody (22C7) was generated with equivalent in vitro affinity and potency against the human and mouse orthologs of the cytokine. This translated into in vivo potency in an IL25-induced air pouch model where 22C7 inhibited the recruitment of monocytes, macrophages, neutrophils and eosinophils. Furthermore, 22C7 significantly reduced ear swelling, acanthosis and disease severity in the Aldara mouse model of psoriasiform skin inflammation. Given the therapeutic potential of IL25 targeting in inflammatory conditions, 22C7 was further engineered to generate a highly developable, fully human antibody while maintaining the affinity and potency of the parental molecule., Conclusions: The generation of 22C7, an anti-IL25 antibody with efficacy in a preclinical model of skin inflammation, raises the therapeutic potential for 22C7 use in the spectrum of IL25-mediated diseases., (© The Author(s) 2022. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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14. Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.
- Author
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Schwartz C, Schmidt V, Deinzer A, Hawerkamp HC, Hams E, Bayerlein J, Röger O, Bailer M, Krautz C, El Gendy A, Elshafei M, Heneghan HM, Hogan AE, O'Shea D, and Fallon PG
- Subjects
- Adipose Tissue metabolism, Animals, Immunity, Innate, Inflammation, Lymphocytes metabolism, Mice, B7-H1 Antigen metabolism, Diet, Obesity metabolism, T-Lymphocytes
- Abstract
Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.
- Published
- 2022
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15. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages.
- Author
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Runtsch MC, Angiari S, Hooftman A, Wadhwa R, Zhang Y, Zheng Y, Spina JS, Ruzek MC, Argiriadi MA, McGettrick AF, Mendez RS, Zotta A, Peace CG, Walsh A, Chirillo R, Hams E, Fallon PG, Jayamaran R, Dua K, Brown AC, Kim RY, Horvat JC, Hansbro PM, Wang C, and O'Neill LAJ
- Subjects
- Janus Kinase 1 metabolism, Janus Kinase 1 pharmacology, Signal Transduction, Succinates, Macrophage Activation, Macrophages metabolism
- Abstract
The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases., Competing Interests: Declaration of interests Y. Zheng, J.S.S., M.C. Ruzek, and M.A.A. are employees and shareholders of AbbVie. All other authors declare no competing interests related to this manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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16. Functions for Retinoic Acid-Related Orphan Receptor Alpha (RORα) in the Activation of Macrophages During Lipopolysaccharide-Induced Septic Shock.
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Hams E, Roberts J, Bermingham R, and Fallon PG
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- Animals, Cells, Cultured, Chemokines metabolism, Disease Models, Animal, Female, Inflammation genetics, Inflammation metabolism, Macrophage Activation drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Receptor Subfamily 1, Group F, Member 1 antagonists & inhibitors, Nuclear Receptor Subfamily 1, Group F, Member 1 genetics, Shock, Septic drug therapy, Signal Transduction drug effects, Signal Transduction genetics, Sulfonamides administration & dosage, Thiophenes administration & dosage, Treatment Outcome, Lipopolysaccharides adverse effects, Macrophage Activation genetics, Macrophages, Peritoneal immunology, Nuclear Receptor Subfamily 1, Group F, Member 1 deficiency, Shock, Septic chemically induced, Shock, Septic immunology
- Abstract
The transcription factor Related Orphan Receptor Alpha (RORα) plays an important role in regulating circadian rhythm, inflammation, metabolism and cellular development. Herein we show that in the absence of functional RORα in mice there is reduced susceptibility to LPS-induced endotoxic shock, with selective decreases in release of pro-inflammatory cytokines. Treatment of mice with a RORα selective synthetic inhibitor also reduced the severity of LPS-induced endotoxemia. The reduction in responses in Rora deficient mice was associated with an alterations in metabolic and pro-inflammatory functions of macrophages, both in vivo peritoneal macrophages and in vitro generated bone marrow derived macrophages. Using LysM
Cre Rorafl/sg mice the reduced susceptibility to LPS was shown to be specific to Rora expression in the macrophages. This study identifies that Rora -mediated regulation of macrophages impacts on the pro-inflammatory responses elicited by LPS., 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 Hams, Roberts, Bermingham and Fallon.)- Published
- 2021
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17. Role for Retinoic Acid-Related Orphan Receptor Alpha (RORα) Expressing Macrophages in Diet-Induced Obesity.
- Author
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Hams E, Roberts J, Bermingham R, Hogan AE, O'Shea D, O'Neill L, and Fallon PG
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- Adipose Tissue metabolism, Animals, Biomarkers, Diet, High-Fat, Disease Models, Animal, Energy Metabolism, Flow Cytometry, Humans, Mice, Mice, Transgenic, Monocytes immunology, Monocytes metabolism, Myeloid Cells immunology, Myeloid Cells metabolism, Obesity pathology, Retinoic Acid Receptor alpha metabolism, Stress, Physiological, Stromal Cells metabolism, Diet, Gene Expression, Macrophages metabolism, Obesity etiology, Obesity metabolism, Retinoic Acid Receptor alpha genetics
- Abstract
The transcription factor RORα plays an important role in regulating circadian rhythm, inflammation, metabolism, and cellular development. Herein we show a role for RORα-expressing macrophages in the adipose tissue in altering the metabolic state of mice on a high-fat diet. The expression of Rora and RORA is elevated in white adipose tissue from obese mice and humans when compared to lean counterparts. When fed a high-fat diet Rora reporter mice revealed increased expression of Rora -YFP in macrophages in white adipose tissue deposits. To further define the potential role for Rora -expressing macrophages in the generation of an aberrant metabolic state Rora
fl/fl LysMCre/+ mice, which do not express Rora in myeloid cells, were maintained on a high-fat diet, and metabolic parameters assessed. These mice had significantly impaired weight gain and improved metabolic parameters in comparison to Rorafl/fl control mice. Further analysis of the immune cell populations within white adipose tissue deposits demonstrates a decrease in inflammatory adipose tissue macrophages (ATM). In obese reporter mouse there was increased in Rora -YFP expressing ATM in adipose tissue. Analysis of peritoneal macrophage populations demonstrates that within the peritoneal cavity Rora -expression is limited to myeloid-derived macrophages, suggesting a novel role for RORα in macrophage development and activation, which can impact on metabolism, and inflammation., (Copyright © 2020 Hams, Roberts, Bermingham, Hogan, O'Shea, O'Neill and Fallon.)- Published
- 2020
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18. Prostate cancer-derived holoclones: a novel and effective model for evaluating cancer stemness.
- Author
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Flynn L, Barr MP, Baird AM, Smyth P, Casey OM, Blackshields G, Greene J, Pennington SR, Hams E, Fallon PG, O'Leary J, Sheils O, and Finn SP
- Subjects
- Animals, Biomarkers, Tumor genetics, Carcinogenesis, Cell Line, Tumor, Humans, Male, Mice, Mice, Inbred NOD, Mice, SCID, Prostatic Neoplasms genetics, Cell Culture Techniques, MicroRNAs genetics, Neoplastic Stem Cells pathology, Prostatic Neoplasms pathology
- Abstract
Prostate cancer accounts for approximately 13.5% of all newly diagnosed male cancer cases. Significant clinical burdens remain in terms of ineffective prognostication, with overtreatment of insignificant disease. Additionally, the pathobiology underlying disease heterogeneity remains poorly understood. As the role of cancer stem cells in the perpetuation of aggressive carcinoma is being substantiated by experimental evidence, it is crucially important to understand the molecular mechanisms, which regulate key features of cancer stem cells. We investigated two methods for in vitro cultivation of putative prostate cancer stem cells based on 'high-salt agar' and 'monoclonal cultivation'. Data demonstrated 'monoclonal cultivation' as the superior method. We demonstrated that 'holoclones' expressed canonical stem markers, retained the exclusive ability to generate poorly differentiated tumours in NOD/SCID mice and possessed a unique mRNA-miRNA gene signature. miRNA:Target interactions analysis visualised potentially critical regulatory networks, which are dysregulated in prostate cancer holoclones. The characterisation of this tumorigenic population lays the groundwork for this model to be used in the identification of proteomic or small non-coding RNA therapeutic targets for the eradication of this critical cellular population. This is significant, as it provides a potential route to limit development of aggressive disease and thus improve survival rates.
- Published
- 2020
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19. Highly efficient CRISPR-targeting of the murine Hipp11 intergenic region supports inducible human transgene expression.
- Author
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Browning J, Rooney M, Hams E, Takahashi S, Mizuno S, Sugiyama F, Fallon PG, and Kelly VP
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- Animals, Antigens, CD1 metabolism, CRISPR-Associated Protein 9 metabolism, Genetic Loci, Genome, Humans, Mice, Transgenic, Clustered Regularly Interspaced Short Palindromic Repeats genetics, DNA, Intergenic genetics, Gene Expression, Transgenes
- Abstract
Safe harbor loci allow predicable integration of a transgene into the genome without perturbing endogenous gene activity and for decades have been exploited in the mouse to investigate gene function, generate humanised models and create tissue specific reporter and Cre recombinase expressing lines. Herein, we show that the murine Hipp11 intergenic region can facilitate highly efficient integration of a large transgene-the human CD1A promoter and coding region-by means of CRISPR-Cas9 mediated homology directed repair. The data shows that the single copy human CD1A transgene is faithfully expressed in an inducible manner in homozygous animals in both macrophage and dendritic cells. Our results validate the Hipp11 intergenic region as being a highly amenable target site for functional transgene integration in mouse.
- Published
- 2020
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20. Correction to: Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer.
- Author
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Barr MP, Gray SG, Gately K, Hams E, Fallon PG, Davies AM, Richard DJ, Pidgeon GP, and O'Byrne KJ
- Abstract
Since the publication of this work [1] and in response to a recent query that was brought to our attention in relation to the Western Blot in Figure 1(C) for NP2, protein lysates prepared around the same time as those presented in the manuscript in question, were run by SDS-PAGE under similar experimental conditions and probed using the same primary antibodies to NP1 and NP2 that were used originally.
- Published
- 2020
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21. Interleukin-36 cytokines alter the intestinal microbiome and can protect against obesity and metabolic dysfunction.
- Author
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Giannoudaki E, Hernandez-Santana YE, Mulfaul K, Doyle SL, Hams E, Fallon PG, Mat A, O'Shea D, Kopf M, Hogan AE, and Walsh PT
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- Akkermansia, Animals, Colon immunology, Colon microbiology, Colon pathology, Diabetes Mellitus, Type 2, Gastrointestinal Microbiome immunology, Gene Expression, Glucose Tolerance Test, Host Microbial Interactions immunology, Host Microbial Interactions physiology, Humans, Inflammation Mediators metabolism, Insulin Resistance, Interleukin-1 genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucin-2 metabolism, Obesity immunology, Receptors, Interleukin-1 genetics, Receptors, Interleukin-1 metabolism, Transcriptome, Verrucomicrobia, Cytokines metabolism, Gastrointestinal Microbiome physiology, Interleukin-1 metabolism, Metabolic Diseases metabolism, Obesity metabolism
- Abstract
Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.
- Published
- 2019
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22. Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM.
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Carty M, Kearney J, Shanahan KA, Hams E, Sugisawa R, Connolly D, Doran CG, Muñoz-Wolf N, Gürtler C, Fitzgerald KA, Lavelle EC, Fallon PG, and Bowie AG
- Subjects
- Animals, Armadillo Domain Proteins genetics, Biomarkers, Cell Survival, Cytoskeletal Proteins genetics, Macrophages immunology, Macrophages metabolism, Mice, Mice, Knockout, Mitochondria genetics, Mitochondria metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Protein Binding, Pyroptosis, Signal Transduction, Armadillo Domain Proteins metabolism, Cytokines metabolism, Cytoskeletal Proteins metabolism, Inflammasomes metabolism
- Abstract
Assembly of inflammasomes after infection or injury leads to the release of interleukin-1β (IL-1β) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1β secretion without cell death, but what controls these different outcomes is unknown. Here, we show that removal of the Toll-IL-1R protein SARM from macrophages uncouples inflammasome-dependent cytokine release and pyroptosis, whereby cells displayed increased IL-1β production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1β release and more pyroptosis. SARM suppressed IL-1β by directly restraining the NLRP3 inflammasome and, hence, caspase-1 activation. Consistent with a role for SARM in pyroptosis, Sarm1
-/- mice were protected from lipopolysaccharide (LPS)-stimulated sepsis. Pyroptosis-inducing, but not hyperactivating, NLRP3 stimulants caused SARM-dependent mitochondrial depolarization. Thus, SARM-dependent mitochondrial depolarization distinguishes NLRP3 activators that cause pyroptosis from those that do not, and SARM modulation represents a cell-intrinsic mechanism to regulate cell fate after inflammasome activation., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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23. Asymmetric synthesis and biological evaluation of imidazole- and oxazole-containing synthetic lipoxin A 4 mimetics (sLXms).
- Author
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de Gaetano M, Butler E, Gahan K, Zanetti A, Marai M, Chen J, Cacace A, Hams E, Maingot C, McLoughlin A, Brennan E, Leroy X, Loscher CE, Fallon P, Perretti M, Godson C, and Guiry PJ
- Subjects
- Animals, Cell Line, Humans, Inflammation drug therapy, Lipoxins pharmacology, Mice, Molecular Mimicry, Monocytes drug effects, Monocytes metabolism, NF-kappa B metabolism, Peritonitis drug therapy, Receptors, Formyl Peptide metabolism, Imidazoles chemistry, Lipoxins chemical synthesis, Oxazoles chemistry
- Abstract
Lipoxins (LXs) are endogenously generated eicosanoids with potent bio-actions consistent with attenuation of inflammation. The costly synthesis and metabolic instability of LXs may limit their therapeutic potential. Here we report the synthesis and characterization of novel imidazole-/oxazole-containing synthetic-LX-mimetics (sLXms). The key steps of asymmetric synthesis of putative sLXms include a Suzuki reaction and an asymmetric ketone reduction. The effect of the novel compounds on inflammatory responses was assessed using a human monocyte cell line stably expressing a Nuclear Factor Kappa B (NFkB) reporter gene, by investigating downstream cytokine secretion. The potential interaction of the imidazoles/oxazoles with the molecular target of LXs, i.e. G-protein coupled receptor (GPCR) Formyl Peptide Receptor 2 (ALX/FPR2) was investigated using a cell system where ALX/FPR2 is coupled to the Gα
q subunit and receptor interaction determined by mobilisation of intracellular calcium. In vivo anti-inflammatory effects were assessed using a murine zymosan-induced peritonitis model. Overall, structure-activity relationship (SAR) studies demonstrated that the (R)-epimer of 6C-dimethyl-imidazole (1R)-11 was the most potent and efficient anti-inflammatory agent, among the ten compounds tested. This molecule significantly attenuated LPS-induced NFkB activity, reduced the release of several pro-inflammatory cytokines and inhibited peritonitis-associated neutrophil infiltration in vivo. The underlying mechanism for those actions appeared to be through FPR2 activation. These data support the therapeutic potential of imidazole-containing sLXms in the context of novel inflammatory regulators., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
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24. Helminth Modulation of Lung Inflammation.
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Schwartz C, Hams E, and Fallon PG
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- Animals, Helminthiasis immunology, Humans, Disease Susceptibility parasitology, Helminthiasis complications, Helminths immunology, Host-Parasite Interactions immunology, Pneumonia complications
- Abstract
Parasitic helminths must establish chronic infections to complete their life cycle and therefore are potent modulators of multiple facets of host physiology. Parasitic helminths have coevolved with humans to become arguably master selectors of our immune system, whereby they have impacted on the selection of genes with beneficial mutations for both host and parasite. While helminth infections of humans are a significant health burden, studies have shown that helminths or helminth products can alter susceptibility to unrelated infectious or inflammatory diseases. This has generated interest in the use of helminth infections or molecules as therapeutics. In this review, we focus on the impact of helminth infections on pulmonary immunity, especially with regard to homeostatic lung function, pulmonary viral and bacterial (co)infections, and asthma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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25. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.
- Author
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Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, Jedrychowski MP, Costa ASH, Higgins M, Hams E, Szpyt J, Runtsch MC, King MS, McGouran JF, Fischer R, Kessler BM, McGettrick AF, Hughes MM, Carroll RG, Booty LM, Knatko EV, Meakin PJ, Ashford MLJ, Modis LK, Brunori G, Sévin DC, Fallon PG, Caldwell ST, Kunji ERS, Chouchani ET, Frezza C, Dinkova-Kostova AT, Hartley RC, Murphy MP, and O'Neill LA
- Subjects
- Alkylation, Animals, Carboxy-Lyases, Cattle, Cysteine chemistry, Cysteine metabolism, Cytokines biosynthesis, Cytokines immunology, Feedback, Physiological, Female, HEK293 Cells, Humans, Hydro-Lyases biosynthesis, Interferon-beta immunology, Interferon-beta pharmacology, Lipopolysaccharides immunology, Lipopolysaccharides pharmacology, Macrophages drug effects, Macrophages metabolism, Mice, Proteins metabolism, Rats, Rats, Wistar, Succinates chemistry, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Kelch-Like ECH-Associated Protein 1 chemistry, Kelch-Like ECH-Associated Protein 1 metabolism, NF-E2-Related Factor 2 agonists, NF-E2-Related Factor 2 metabolism, Succinates metabolism
- Abstract
The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.
- Published
- 2018
- Full Text
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26. The vaccine adjuvant alum promotes IL-10 production that suppresses Th1 responses.
- Author
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Oleszycka E, McCluskey S, Sharp FA, Muñoz-Wolf N, Hams E, Gorman AL, Fallon PG, and Lavelle EC
- Subjects
- Animals, Cells, Cultured, Escherichia coli immunology, Female, Interleukin-10 biosynthesis, Interleukin-10 genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Vaccines immunology, Adjuvants, Immunologic pharmacology, Alum Compounds pharmacology, Dendritic Cells immunology, Interleukin-10 immunology, Macrophages immunology, Monocytes immunology, Th1 Cells immunology
- Abstract
The effectiveness of many vaccines licensed for clinical use relates to the induction of neutralising antibodies, facilitated by the inclusion of vaccine adjuvants, particularly alum. However, the ability of alum to preferentially promote humoral rather than cellular, particularly Th1-type responses, is not well understood. We demonstrate that alum activates immunosuppressive mechanisms following vaccination, which limit its capacity to induce Th1 responses. One of the key cytokines limiting excessive immune responses is IL-10. Injection of alum primed draining lymph node cells for enhanced IL-10 secretion ex vivo. Moreover, at the site of injection, macrophages and dendritic cells were key sources of IL-10 expression. Alum strongly enhanced the transcription and secretion of IL-10 by macrophages and dendritic cells. The absence of IL-10 signalling did not compromise alum-induced cell infiltration into the site of injection, but resulted in enhanced antigen-specific Th1 responses after vaccination. In contrast to its decisive regulatory role in regulating Th1 responses, there was no significant change in antigen-specific IgG1 antibody production following vaccination with alum in IL-10-deficient mice. Overall, these findings indicate that injection of alum promotes IL-10, which can block Th1 responses and may explain the poor efficacy of alum as an adjuvant for inducing protective Th1 immunity., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
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27. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis.
- Author
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Cooke G, Kamal I, Strengert M, Hams E, Mawhinney L, Tynan A, O'Reilly C, O'Dwyer DN, Kunkel SL, Knaus UG, Shields DC, Moller DR, Bowie AG, Fallon PG, Hogaboam CM, Armstrong ME, and Donnelly SC
- Subjects
- Adolescent, Adult, Aged, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Ireland, Logistic Models, Male, Middle Aged, Phenotype, Young Adult, Polymorphism, Single Nucleotide, Sarcoidosis, Pulmonary genetics, Toll-Like Receptor 3 genetics
- Abstract
Background/introduction: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available., Aim: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients., Design: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis., Methods: Cohorts of Irish sarcoidosis patients (n = 228), healthy Irish controls (n = 263) and a secondary cohort of American sarcoidosis patients (n = 123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses., Results: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-β and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients., Discussion/conclusion: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker.
- Published
- 2018
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28. ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control.
- Author
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Schwartz C, Khan AR, Floudas A, Saunders SP, Hams E, Rodewald HR, McKenzie ANJ, and Fallon PG
- Subjects
- Adaptive Immunity immunology, Adaptive Immunity physiology, Animals, B7-H1 Antigen immunology, GATA3 Transcription Factor physiology, Immunity, Cellular immunology, Immunity, Cellular physiology, Interleukin-13 physiology, Lymphocytes immunology, Mice, Mice, Inbred C57BL, Nippostrongylus immunology, Strongylida Infections immunology, Th2 Cells immunology, B7-H1 Antigen physiology, Lymphocytes physiology, Th2 Cells physiology
- Abstract
Group 2 innate lymphoid cells (ILC2s) are important effector cells driving the initiation of type 2 immune responses leading to adaptive T helper 2 (Th2) immunity. Here we show that ILC2s dynamically express the checkpoint inhibitor molecule PD-L1 during type 2 pulmonary responses. Surprisingly, PD-L1:PD-1 interaction between ILC2s and CD4
+ T cells did not inhibit the T cell response, but PD-L1-expressing ILC2s stimulated increased expression of GATA3 and production of IL-13 by Th2 cells both in vitro and in vivo. Conditional deletion of PD-L1 on ILC2s impaired early Th2 polarization and cytokine production, leading to delayed worm expulsion during infection with the gastrointestinal helminth Nippostrongylus brasiliensis Our results identify a novel PD-L1-controlled mechanism for type 2 polarization, with ILC2s mediating an innate checkpoint to control adaptive T helper responses, which has important implications for the treatment of type 2 inflammation., (© 2017 Schwartz et al.)- Published
- 2017
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29. IL-17 Receptor A Maintains and Protects the Skin Barrier To Prevent Allergic Skin Inflammation.
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Floudas A, Saunders SP, Moran T, Schwartz C, Hams E, Fitzgerald DC, Johnston JA, Ogg GS, McKenzie AN, Walsh PT, and Fallon PG
- Subjects
- Animals, Cytokines immunology, Dermatitis, Atopic pathology, Disease Models, Animal, Dysbiosis, Eosinophilia immunology, Filaggrin Proteins, Gene Expression Regulation, Homeostasis, Interleukin-33 immunology, Interleukin-5 genetics, Interleukin-5 immunology, Interleukins genetics, Interleukins immunology, Intermediate Filament Proteins deficiency, Intermediate Filament Proteins genetics, Mice, Microbiota, Mutation, Receptors, Antigen, T-Cell, gamma-delta immunology, Receptors, Interleukin-17 deficiency, Receptors, Interleukin-17 genetics, Signal Transduction, Skin immunology, Skin microbiology, Th2 Cells immunology, Thymic Stromal Lymphopoietin, Interleukin-22, Dermatitis, Atopic immunology, Receptors, Interleukin-17 immunology, Receptors, Interleukin-17 metabolism, Skin growth & development, Skin pathology
- Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency ( Il17ra
-/- ) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra-/- mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra-/- mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra-/- mice was dependent on TSLP, but not the other alarmins IL-25 and IL-33. The associated skin inflammation was mediated by IL-5-expressing pathogenic effector Th2 cells and was independent of TCRγδ T cells and IL-22. An absence of IL-17RA in nonhematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin-infiltrating pathogenic effector Th2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signaling in regulation of the skin barrier and maintenance of skin immune homeostasis., (Copyright © 2017 by The American Association of Immunologists, Inc.)- Published
- 2017
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30. Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung.
- Author
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de Kleer IM, Kool M, de Bruijn MJ, Willart M, van Moorleghem J, Schuijs MJ, Plantinga M, Beyaert R, Hams E, Fallon PG, Hammad H, Hendriks RW, and Lambrecht BN
- Subjects
- Animals, Animals, Newborn, Disease Models, Animal, Hypersensitivity immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Pyroglyphidae immunology, Signal Transduction immunology, Asthma immunology, Interleukin-33 immunology, Lung growth & development, Lung immunology, Th2 Cells immunology
- Abstract
Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b
+ dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2016
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31. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages.
- Author
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Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R, Iwamoto H, Yang X, Nakamura M, Wang J, Zhuang R, Morikawa H, Xue Y, Braun H, Beyaert R, Samani N, Nakae S, Hams E, Dissing S, Fallon PG, Langer R, and Cao Y
- Subjects
- Animals, Becaplermin, Cell Line, Tumor, Female, Humans, Interleukin-33 genetics, Mice, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, SOXF Transcription Factors genetics, Interleukin-33 metabolism, Macrophages metabolism, Pericytes metabolism, Proto-Oncogene Proteins c-sis metabolism, SOXF Transcription Factors metabolism, Stromal Cells metabolism
- Abstract
Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.
- Published
- 2016
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- View/download PDF
32. Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity.
- Author
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Saunders SP, Moran T, Floudas A, Wurlod F, Kaszlikowska A, Salimi M, Quinn EM, Oliphant CJ, Núñez G, McManus R, Hams E, Irvine AD, McKenzie AN, Ogg GS, and Fallon PG
- Subjects
- Animals, Dermatitis, Atopic genetics, Dermatitis, Atopic pathology, Disease Models, Animal, Filaggrin Proteins, Intermediate Filament Proteins deficiency, Intermediate Filament Proteins genetics, Lymphocytes immunology, Lymphocytes metabolism, Lymphocytes pathology, Mice, Mice, Transgenic, Mutation, Phenotype, Pneumonia pathology, Skin immunology, Skin metabolism, Skin pathology, Adaptive Immunity, Dermatitis, Atopic complications, Dermatitis, Atopic immunology, Immunity, Innate, Pneumonia etiology
- Abstract
Background: Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma., Objective: We sought to experimentally address whether filaggrin mutations in mice lead to the development of spontaneous eczematous inflammation and address the aberrant immunologic milieu arising in a mouse model of filaggrin deficiency., Methods: Filaggrin mutant mice were generated on the proallergic BALB/c background, creating a novel model for the assessment of spontaneous AD-like inflammation. Independently recruited AD case collections were analyzed to define associations between filaggrin mutations and immunologic phenotypes., Results: Filaggrin-deficient mice on a BALB/c background had profound spontaneous AD-like inflammation with progression to compromised pulmonary function with age, reflecting the atopic march in patients with AD. Strikingly, skin inflammation occurs independently of adaptive immunity and is associated with cutaneous expansion of IL-5-producing type 2 innate lymphoid cells. Furthermore, subjects with filaggrin mutations have an increased frequency of type 2 innate lymphoid cells in the skin in comparison with control subjects., Conclusion: This study provides new insights into our understanding of the atopic march, with innate immunity initiating dermatitis and the adaptive immunity required for subsequent development of compromised lung function., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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- View/download PDF
33. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism.
- Author
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Hams E, Bermingham R, Wurlod FA, Hogan AE, O'Shea D, Preston RJ, Rodewald HR, McKenzie AN, and Fallon PG
- Subjects
- Animals, Eosinophils immunology, Interleukin-33 genetics, Lectins, C-Type immunology, Macrophage Activation genetics, Macrophages immunology, Mannose Receptor, Mannose-Binding Lectins immunology, Mice, Mice, Knockout, Mice, Obese, Obesity genetics, Obesity immunology, Receptors, Cell Surface immunology, Schistosoma mansoni enzymology, Antigens, Helminth immunology, Egg Proteins immunology, Helminth Proteins immunology, Immunity, Innate, Interleukin-33 immunology, Lymphocytes immunology, Ribonucleases immunology, Schistosoma mansoni immunology
- Abstract
Induction of a type 2 cellular response in the white adipose tissue leads to weight loss and improves glucose homeostasis in obese animals. Injection of obese mice with recombinant helminth-derived Schistosoma mansoni egg-derived ω1 (ω1), a potent inducer of type 2 activation, improves metabolic status involving a mechanism reliant upon release of the type 2 initiator cytokine IL-33. IL-33 initiates the accumulation of group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages in the adipose tissue. IL-33 release from cells in the adipose tissue is mediated by the RNase activity of ω1; however, the ability of ω1 to improve metabolic status is reliant upon effective binding of ω1 to CD206. We demonstrate a novel mechanism for RNase-mediated release of IL-33 inducing ILC2-dependent improvements in the metabolic status of obese animals., (© FASEB.)
- Published
- 2016
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- View/download PDF
34. Macrophage and Innate Lymphoid Cell Interplay in the Genesis of Fibrosis.
- Author
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Hams E, Bermingham R, and Fallon PG
- Abstract
Fibrosis is a characteristic pathological feature of an array of chronic diseases, where development of fibrosis in tissue can lead to marked alterations in the architecture of the affected organs. As a result of this process of sustained attrition to organs, many diseases that involve fibrosis are often progressive conditions and have a poor long-term prognosis. Inflammation is often a prelude to fibrosis, with innate and adaptive immunity involved in both the initiation and regulation of the fibrotic process. In this review, we will focus on the emerging roles of the newly described innate lymphoid cells (ILCs) in the generation of fibrotic disease with an examination of the potential interplay between ILC and macrophages and the adaptive immune system.
- Published
- 2015
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35. Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation.
- Author
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Spence S, Greene MK, Fay F, Hams E, Saunders SP, Hamid U, Fitzgerald M, Beck J, Bains BK, Smyth P, Themistou E, Small DM, Schmid D, O'Kane CM, Fitzgerald DC, Abdelghany SM, Johnston JA, Fallon PG, Burrows JF, McAuley DF, Kissenpfennig A, and Scott CJ
- Subjects
- Animals, Humans, Interleukin-10 physiology, Mice, Mice, Inbred C57BL, Sialic Acid Binding Immunoglobulin-like Lectins metabolism, Up-Regulation, Inflammation prevention & control, N-Acetylneuraminic Acid chemistry, Nanoparticles, Sialic Acid Binding Immunoglobulin-like Lectins drug effects
- Abstract
Sepsis is the most frequent cause of death in hospitalized patients, and severe sepsis is a leading contributory factor to acute respiratory distress syndrome (ARDS). At present, there is no effective treatment for these conditions, and care is primarily supportive. Murine sialic acid-binding immunoglobulin-like lectin-E (Siglec-E) and its human orthologs Siglec-7 and Siglec-9 are immunomodulatory receptors found predominantly on hematopoietic cells. These receptors are important negative regulators of acute inflammatory responses and are potential targets for the treatment of sepsis and ARDS. We describe a Siglec-targeting platform consisting of poly(lactic-co-glycolic acid) nanoparticles decorated with a natural Siglec ligand, di(α2→8) N-acetylneuraminic acid (α2,8 NANA-NP). This nanoparticle induced enhanced oligomerization of the murine Siglec-E receptor on the surface of macrophages, unlike the free α2,8 NANA ligand. Furthermore, treatment of murine macrophages with these nanoparticles blocked the production of lipopolysaccharide-induced inflammatory cytokines in a Siglec-E-dependent manner. The nanoparticles were also therapeutically beneficial in vivo in both systemic and pulmonary murine models replicating inflammatory features of sepsis and ARDS. Moreover, we confirmed the anti-inflammatory effect of these nanoparticles on human monocytes and macrophages in vitro and in a human ex vivo lung perfusion (EVLP) model of lung injury. We also established that interleukin-10 (IL-10) induced Siglec-E expression and α2,8 NANA-NP further augmented the expression of IL-10. Indeed, the effectiveness of the nanoparticle depended on IL-10. Collectively, these results demonstrated a therapeutic effect of targeting Siglec receptors with a nanoparticle-based platform under inflammatory conditions., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
- Full Text
- View/download PDF
36. Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells.
- Author
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Khan AR, Amu S, Saunders SP, Hams E, Blackshields G, Leonard MO, Weaver CT, Sparwasser T, Sheils O, and Fallon PG
- Subjects
- Animals, Antigens, CD19 metabolism, Antigens, CD1d metabolism, Disease Models, Animal, Humans, Hypersensitivity immunology, Hypersensitivity metabolism, Interleukin-10 biosynthesis, Mice, Mice, Knockout, Ovalbumin adverse effects, Pneumonia parasitology, Protein Binding, Respiratory Hypersensitivity immunology, Respiratory Hypersensitivity metabolism, Respiratory Hypersensitivity parasitology, Schistosoma mansoni immunology, Schistosomiasis mansoni immunology, Schistosomiasis mansoni metabolism, Up-Regulation, B-Lymphocytes immunology, B-Lymphocytes metabolism, Pneumonia immunology, Pneumonia metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Toll-Like Receptor 7 metabolism
- Abstract
B cells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19(+) CD1d(hi) cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19(+) CD1d(hi) B cells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19(+) CD1d(hi) B cells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10(-/-) and Tlr7(-/-) mice, we formally demonstrate that TLR7 ligation of CD19(+) CD1d(hi) B cells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19(+) CD1d(hi) B cells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3(+) T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19(+) CD1d(hi) B cells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19(+) CD1d(hi) B cells, which can suppress allergic lung inflammation via T regulatory cells., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
- Full Text
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37. Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer.
- Author
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Barr MP, Gray SG, Gately K, Hams E, Fallon PG, Davies AM, Richard DJ, Pidgeon GP, and O'Byrne KJ
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Down-Regulation genetics, Female, Humans, MAP Kinase Signaling System genetics, Mice, Mice, Inbred BALB C, Mice, Nude, Mitogen-Activated Protein Kinase Kinases genetics, Phosphatidylinositol 3-Kinases genetics, Receptors, Vascular Endothelial Growth Factor genetics, C-Reactive Protein genetics, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics, Nerve Tissue Proteins genetics, Signal Transduction genetics, Vascular Endothelial Growth Factor A genetics
- Abstract
Background: The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process., Methods: NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells., Results: Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls., Conclusions: Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.
- Published
- 2015
- Full Text
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38. PD-L1hi B cells are critical regulators of humoral immunity.
- Author
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Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, and Fallon PG
- Subjects
- Adult, Animals, Antibodies, Monoclonal chemistry, Autoimmunity, B-Lymphocytes, Regulatory immunology, B7-H1 Antigen physiology, CD4-Positive T-Lymphocytes cytology, Cell Differentiation, Cell Separation, Cytokines metabolism, Encephalomyelitis, Autoimmune, Experimental immunology, Female, Homeostasis, Humans, Immune System, Immunoglobulin G immunology, Inflammation, Interleukin-10 metabolism, Mice, Mice, Inbred C57BL, Receptors, CXCR5 metabolism, Young Adult, B-Lymphocytes, Regulatory cytology, B7-H1 Antigen biosynthesis, Immunity, Humoral immunology, Programmed Cell Death 1 Receptor metabolism
- Abstract
Specific B-cell subsets can regulate T-cell immune responses, and are termed regulatory B cells (Breg). The majority of Breg cells described in mouse and man have been identified by IL-10 production and are known to suppress allergy and autoimmunity. However, Breg cell mediated immune suppression, independent of IL-10, also occurs. Here we show that Breg cells play a critical role in regulating humoral immunity mediated by CD4(+)CXCR5(+)PD-1(+) follicular helper T cells, and can suppress inflammation in autoimmune disease through elevated expression of PD-L1. We have also identified that these B cells are resistant to αCD20 B-cell depletion. This work describes how Breg cells are critical in humoral homoeostasis and may have implications for the regulation of autoimmune diseases.
- Published
- 2015
- Full Text
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39. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion.
- Author
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Oliphant CJ, Hwang YY, Walker JA, Salimi M, Wong SH, Brewer JM, Englezakis A, Barlow JL, Hams E, Scanlon ST, Ogg GS, Fallon PG, and McKenzie AN
- Subjects
- Animals, Antigen Presentation immunology, Cell Differentiation immunology, Cell Proliferation, Cells, Cultured, Coculture Techniques, Dendritic Cells immunology, Histocompatibility Antigens Class II genetics, Immunity, Cellular, Immunity, Innate, Interleukin-13 biosynthesis, Interleukin-13 metabolism, Interleukin-2 biosynthesis, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Cell Communication immunology, Histocompatibility Antigens Class II immunology, Nippostrongylus immunology, Th2 Cells immunology
- Abstract
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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40. IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration.
- Author
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Doyle SL, Ozaki E, Brennan K, Humphries MM, Mulfaul K, Keaney J, Kenna PF, Maminishkis A, Kiang AS, Saunders SP, Hams E, Lavelle EC, Gardiner C, Fallon PG, Adamson P, Humphries P, and Campbell M
- Subjects
- Animals, Autophagy drug effects, Cell Line, Cell Survival drug effects, Choroidal Neovascularization complications, Choroidal Neovascularization pathology, Hematopoiesis drug effects, Humans, Interleukin-18 pharmacology, Interleukin-1beta pharmacology, Interleukin-1beta therapeutic use, Intravitreal Injections, Lasers, Macular Degeneration complications, Macular Degeneration pathology, Mice, Models, Biological, Permeability drug effects, Retinal Pigment Epithelium drug effects, Retinal Pigment Epithelium pathology, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Choroidal Neovascularization drug therapy, Choroidal Neovascularization prevention & control, Interleukin-18 therapeutic use, Macular Degeneration drug therapy
- Abstract
Age-related macular degeneration (AMD) is the most common form of central retinal blindness globally. Distinct processes of the innate immune system, specifically activation of the NLRP3 inflammasome, have been shown to play a central role in the development of both "dry" and neovascular ("wet") forms of the disease. We show that the inflammatory cytokine interleukin-18 (IL-18) can regulate choroidal neovascularization formation in mice. We observed that exogenous administration of mature recombinant IL-18 has no effect on retinal pigment epithelial (RPE) cell viability, but that overexpression of pro-IL-18 or pro-IL-1β alone can cause RPE cell swelling and subsequent atrophy, a process that can be inhibited by the promotion of autophagy. A direct comparison of local and systemic administration of mature recombinant IL-18 with current anti-VEGF (vascular endothelial growth factor)-based therapeutic strategies shows that IL-18 treatment works effectively alone and more effectively in combination with anti-VEGF therapy and represents a novel therapeutic strategy for the treatment of wet AMD.
- Published
- 2014
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41. Btk regulates macrophage polarization in response to lipopolysaccharide.
- Author
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Ní Gabhann J, Hams E, Smith S, Wynne C, Byrne JC, Brennan K, Spence S, Kissenpfennig A, Johnston JA, Fallon PG, and Jefferies CA
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Animals, Hypersensitivity complications, Hypersensitivity enzymology, Hypersensitivity pathology, Inflammation complications, Inflammation enzymology, Inflammation pathology, Lipopolysaccharides pharmacology, Macrophages drug effects, Macrophages, Peritoneal cytology, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal enzymology, Mice, Mice, Inbred C57BL, Models, Biological, Phenotype, Phosphorylation drug effects, Protein-Tyrosine Kinases deficiency, Signal Transduction drug effects, Toll-Like Receptor 4 metabolism, Transcription, Genetic drug effects, Cell Polarity drug effects, Macrophages cytology, Macrophages enzymology, Protein-Tyrosine Kinases metabolism
- Abstract
Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (-\-)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(-/-) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(-/-) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(-/-) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (-/-) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation.
- Published
- 2014
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- View/download PDF
42. Interleukin-6 signaling drives fibrosis in unresolved inflammation.
- Author
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Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, Williams AS, Lambie M, Foster TL, Liao CT, Rice CM, Greenhill CJ, Colmont CS, Hams E, Coles B, Kift-Morgan A, Newton Z, Craig KJ, Williams JD, Williams GT, Davies SJ, Humphreys IR, O'Donnell VB, Taylor PR, Jenkins BJ, Topley N, and Jones SA
- Subjects
- Acute Disease, Adoptive Transfer, Animals, Cells, Cultured, Chronic Disease, Disease Models, Animal, Extracellular Matrix immunology, Feedback, Physiological, Fibrosis, Humans, Interferon-gamma genetics, Interferon-gamma metabolism, Interleukin-6 genetics, Interleukin-6 immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, Signal Transduction, Th1 Cells transplantation, Interleukin-6 metabolism, Peritoneum pathology, Peritonitis genetics, Peritonitis pathology, Th1 Cells immunology
- Abstract
Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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43. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis.
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Hams E, Armstrong ME, Barlow JL, Saunders SP, Schwartz C, Cooke G, Fahy RJ, Crotty TB, Hirani N, Flynn RJ, Voehringer D, McKenzie AN, Donnelly SC, and Fallon PG
- Subjects
- Aged, Animals, Cell Adhesion Molecules metabolism, Collagen chemistry, Collagen metabolism, Female, Humans, Idiopathic Pulmonary Fibrosis pathology, Immunity, Innate, Inflammation, Interleukin-13 metabolism, Liver parasitology, Lung metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Middle Aged, Pulmonary Fibrosis pathology, Schistosoma mansoni, Gene Expression Regulation, Interleukin-17 metabolism, Interleukins metabolism, Lymphocytes cytology, Pulmonary Fibrosis metabolism
- Abstract
Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell-mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.
- Published
- 2014
- Full Text
- View/download PDF
44. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from lipopolysaccharide-stimulated myeloid cells.
- Author
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Gleeson EM, O'Donnell JS, Hams E, Ní Áinle F, Kenny BA, Fallon PG, and Preston RJ
- Subjects
- Androstadienes pharmacology, Animals, Cell Line, Enzyme Activation drug effects, Factor Xa chemistry, Humans, Lipopolysaccharides immunology, Macrophages immunology, Macrophages metabolism, Mice, Mice, Knockout, Myeloid Cells immunology, NF-kappa B metabolism, Protein Interaction Domains and Motifs, Receptor, PAR-2 genetics, Wortmannin, Cytokines biosynthesis, Factor Xa metabolism, Inflammation Mediators metabolism, Myeloid Cells metabolism, Receptor, PAR-2 metabolism, Signal Transduction drug effects
- Abstract
Vitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated, receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known. In this study, exposure to factor Xa significantly impaired pro-inflammatory cytokine production from lipopolysaccharide-treated peripheral blood mononuclear cells, THP-1 monocytic cells and murine macrophages. Furthermore, factor Xa inhibited nuclear factor-kappa B activation in THP-1 reporter cells, requiring phosphatidylinositide 3-kinase activity for its anti-inflammatory effect. Active-site blockade, γ-carboxyglutamic acid domain truncation and a peptide mimic of the factor Xa inter-epidermal growth factor-like region prevented factor Xa inhibition of lipopolysaccharide-induced tumor necrosis factor-α release. In addition, factor Xa anti-inflammatory activity was markedly attenuated by the presence of an antagonist of protease-activated receptor 2, but not protease-activated receptor 1. The key role of protease-activated receptor 2 in eliciting factor Xa-dependent anti-inflammatory signaling on macrophages was further underscored by the inability of factor Xa to mediate inhibition of tumor necrosis factor-α and interleukin-6 release from murine bone marrow-derived protease-activated receptor 2-deficient macrophages. We also show for the first time that, in addition to protease-activated receptor 2, factor Xa requires a receptor-associated protein-sensitive low-density lipoprotein receptor to inhibit lipopolysaccharide-induced cytokine production. Collectively, the findings of this study support a novel function for factor Xa as an endogenous, receptor-associated protein-sensitive, protease-activated receptor 2-dependent regulator of myeloid cell pro-inflammatory cytokine production.
- Published
- 2014
- Full Text
- View/download PDF
45. Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice.
- Author
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Hams E, Locksley RM, McKenzie AN, and Fallon PG
- Subjects
- Adoptive Transfer, Animals, Cell Movement, Glucose immunology, Glucose metabolism, Homeodomain Proteins genetics, Homeostasis, Immunity, Innate, Immunomodulation, Interleukin-13 immunology, Macrophages immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity genetics, Interleukins immunology, Intra-Abdominal Fat immunology, Lymphocyte Subsets immunology, Natural Killer T-Cells immunology, Obesity immunology, Th2 Cells immunology
- Abstract
The cellular composition of visceral adipose tissue (VAT) and release of cytokines by such cells within VAT has been implicated in regulating obesity and metabolic homeostasis. We show the importance of IL-25-responsive innate cells, which release the Th2 cytokine IL-13, in regulating weight and glucose homeostasis in mouse models of diet-induced obesity. Treating obese mice with IL-25 induces weight loss and improves glucose tolerance, and is associated with increased infiltration of innate lymphoid type 2 cells (ILC2), type I and type II NKT cells, eosinophils, and alternatively activated macrophages into the VAT. By depleting ILC2 in obese Rag1(-/-) mice, we observe exacerbated weight gain and glucose intolerance. Conversely, transferring ILC2 or type I or type II NKT cells into obese mice induces transient weight loss and stabilizes glucose homeostasis. Our data identify a mechanism whereby IL-25 eliciting IL-13-producing innate cells regulates inflammation in adipose tissue and prevents diet-induced obesity.
- Published
- 2013
- Full Text
- View/download PDF
46. Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways.
- Author
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Scholz CC, Cavadas MA, Tambuwala MM, Hams E, Rodríguez J, von Kriegsheim A, Cotter P, Bruning U, Fallon PG, Cheong A, Cummins EP, and Taylor CT
- Subjects
- Analysis of Variance, Blotting, Western, HeLa Cells, Humans, Hydroxylation, Hypoxia metabolism, Immunoprecipitation, Inflammation metabolism, Interleukin-1beta metabolism, Luciferases, Mass Spectrometry, Prolyl Hydroxylases metabolism, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins metabolism, Gene Expression Regulation physiology, Hypoxia physiopathology, Inflammation physiopathology, Mixed Function Oxygenases metabolism, NF-kappa B metabolism, Signal Transduction physiology
- Abstract
Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor κB (NF-κB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1β, a major proinflammatory cytokine that regulates NF-κB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1β-induced NF-κB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1β-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1β signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1β-dependent inflammatory signaling.
- Published
- 2013
- Full Text
- View/download PDF
47. The schistosoma granuloma: friend or foe?
- Author
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Hams E, Aviello G, and Fallon PG
- Abstract
Infection of man with Schistosoma species of trematode parasite causes marked chronic morbidity. Individuals that become infected with Schistosomes may develop a spectrum of pathology ranging from mild cercarial dermatitis to severe tissue inflammation, in particular within the liver and intestines, which can lead to life threatening hepatosplenomegaly. It is well established that the etiopathology during schistosomiasis is primarily due to an excessive or unregulated inflammatory response to the parasite, in particular to eggs that become trapped in various tissue. The eggs forms the foci of a classical type 2 granulomatous inflammation, characterized by an eosinophil-rich, CD4(+) T helper (Th) 2 cell dominated infiltrate with additional infiltration of alternatively activated macrophages (M2). Indeed the sequela of the type 2 perioval granuloma is marked fibroblast infiltration and development of fibrosis. Paradoxically, while the granuloma is the cause of pathology it also can afford some protection, whereby the granuloma minimizes collateral tissue damage in the liver and intestines. Furthermore, the parasite is exquisitely reliant on the host to mount a granulomatous reaction to the eggs as this inflammatory response facilitates the successful excretion of the eggs from the host. In this focused review we will address the conundrum of the S. mansoni granuloma acting as both friend and foe in inflammation during infection.
- Published
- 2013
- Full Text
- View/download PDF
48. Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization.
- Author
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Spence S, Fitzsimons A, Boyd CR, Kessler J, Fitzgerald D, Elliott J, Gabhann JN, Smith S, Sica A, Hams E, Saunders SP, Jefferies CA, Fallon PG, McAuley DF, Kissenpfennig A, and Johnston JA
- Subjects
- Adoptive Transfer, Animals, Gene Expression Regulation, Interleukin-10 immunology, Interleukin-10 metabolism, Macrophages transplantation, Mice, STAT Transcription Factors metabolism, Sepsis genetics, Sepsis immunology, Sepsis prevention & control, Signal Transduction, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins immunology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Transplantation, Isogeneic, Cell Polarity genetics, Macrophages immunology, Macrophages metabolism, Suppressor of Cytokine Signaling Proteins genetics
- Abstract
Suppressors of cytokine signaling (SOCS) are important regulators of lipopolysaccharide (LPS) and cytokine responses but their role in macrophage polarization is unknown. We have shown here that myeloid-restricted Socs3 deletion (Socs3(Lyz2cre)) resulted in resistance to LPS-induced endotoxic shock, whereas Socs2(-/-) mice were highly susceptible. We observed striking bias toward M2-like macrophages in Socs3(Lyz2cre) mice, whereas the M1-like population was enriched in Socs2(-/-) mice. Adoptive transfer experiments showed that responses to endotoxic shock and polymicrobial sepsis were transferable and macrophage dependent. Critically, this dichotomous response was associated with enhanced regulatory T (Treg) cell recruitment by Socs3(Lyz2cre) cells, whereas Treg cell recruitment was absent in the presence of Socs2(-/-) macrophages. In addition, altered polarization coincided with enhanced interferon-gamma (IFN-γ)-induced signal transducer and activator of transcription-1 (STAT1) activation in Socs2(-/-) macrophages and enhanced interleukin-4 (IL-4) plus IL-13-induced STAT6 phosphorylation in Socs3(Lyz2cre) macrophages. SOCS, therefore, are essential controllers of macrophage polarization, regulating inflammatory responses., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
49. Cutting edge: suppression of GM-CSF expression in murine and human T cells by IL-27.
- Author
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Young A, Linehan E, Hams E, O'Hara Hall AC, McClurg A, Johnston JA, Hunter CA, Fallon PG, and Fitzgerald DC
- Subjects
- Animals, Cell Polarity genetics, Cell Polarity immunology, Cells, Cultured, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Humans, Inflammation Mediators pharmacology, Inflammation Mediators physiology, Interleukin-17 pharmacology, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets pathology, Toxoplasmosis immunology, Toxoplasmosis pathology, Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors, Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis, Immune Tolerance genetics, Interleukin-17 physiology, T-Lymphocyte Subsets immunology
- Abstract
GM-CSF is a potent proinflammatory cytokine that plays a pathogenic role in the CNS inflammatory disease experimental autoimmune encephalomyelitis. As IL-27 alleviates experimental autoimmune encephalomyelitis, we hypothesized that IL-27 suppresses GM-CSF expression by T cells. We found that IL-27 suppressed GM-CSF expression in CD4+ and CD8+ T cells in splenocyte and purified T cell cultures. IL-27 suppressed GM-CSF in Th1, but not Th17, cells. IL-27 also suppressed GM-CSF expression by human T cells in nonpolarized and Th1- but not Th17-polarized PBMC cultures. In vivo, IL-27p28 deficiency resulted in increased GM-CSF expression by CNS-infiltrating T cells during Toxoplasma gondii infection. Although in vitro suppression of GM-CSF by IL-27 was independent of IL-2 suppression, IL-10 upregulation, or SOCS3 signaling, we observed that IL-27-driven suppression of GM-CSF was STAT1 dependent. Our findings demonstrate that IL-27 is a robust negative regulator of GM-CSF expression in T cells, which likely inhibits T cell pathogenicity in CNS inflammation.
- Published
- 2012
- Full Text
- View/download PDF
50. Innate type 2 cells and asthma.
- Author
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Hams E and Fallon PG
- Subjects
- Animals, Cytokines immunology, Humans, Pneumonia immunology, Asthma immunology, Th2 Cells immunology
- Abstract
Asthma and other allergic conditions are immunologically described as Th2 skewed, with associated increases in IgE, eosinophila and expression of IL-4, IL-5 and IL-13. However, recent advances have implicated other type 2 cytokines such as IL-25, IL-33 and TSLP in the pathogenesis of allergic conditions. These cytokines are potent inducers of the panel of recently described innate immune cells, which also produce large amounts of the Th2 cytokines IL-5 and IL-13 independent of the adaptive immune response. We review herein, the role for these innate cell populations with a focus on the nuocyte, in allergic asthma and pulmonary inflammation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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