69 results on '"Bosurgi, L"'
Search Results
2. Impact of portal hypertension on epithelial cell death markers in patients with decompensated liver cirrhosis
- Author
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Piecha, F., additional, Jahn, B.-V., additional, Köntopf, J., additional, Koop, A., additional, Ozga, A.-K., additional, Al-Jawazneh, A., additional, Harberts, A., additional, Riedel, C., additional, Buggisch, P., additional, Hübener, P., additional, Bosurgi, L., additional, Benten, D., additional, Huber, S., additional, Lohse, A. W., additional, Bannas, P., additional, and Kluwe, J., additional
- Published
- 2023
- Full Text
- View/download PDF
3. Resolution of portal hypertension by insertion of a transjugular intrahepatic portosystemic shunt (TIPS) ameliorates markers of gut barrier function, systemic hyperinflammation and reverses phenotypic alterations of monocytes in patients with decompensated liver cirrhosis
- Author
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Piecha, F., additional, Al-Jawazneh, A., additional, Jahn, B.-V., additional, Köntopf, J., additional, Koop, A., additional, Buescher, G., additional, Harberts, A., additional, Benten, D., additional, Riedel, C., additional, Buggisch, P., additional, Hübener, P., additional, Huber, S., additional, Lohse, A. W., additional, Bannas, P., additional, Bosurgi, L., additional, and Kluwe, J., additional
- Published
- 2023
- Full Text
- View/download PDF
4. 10:30-10:40 Prenatal acetaminophen exposure distorts ovarian macrophages with long lasting consequences for gonadal function
- Author
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Bazzano, MV, primary, Berkout, L, additional, Bremmer, L, additional, Weber, F, additional, Hardardottir, L, additional, Promm, M, additional, Köninger, A, additional, Arck, PC, additional, Bosurgi, L, additional, Tiegs, G, additional, and Solano, ME, additional
- Published
- 2023
- Full Text
- View/download PDF
5. Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation
- Author
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Theobald, H., primary, Bejarano, D.A., additional, Katzmarski, N., additional, Haub, J., additional, Schulte-Schrepping, J., additional, Yu, J., additional, Bassler, K, additional, Ćirović, B., additional, Osei-Sarpong, C., additional, Piattini, F., additional, Vornholz, L, additional, Yu, X., additional, Sheoran, S., additional, Al Jawazneh, A., additional, Chakarov, S., additional, Haendler, K, additional, Brown, G.D., additional, Williams, D.L., additional, Bosurgi, L., additional, Ginhoux, F., additional, Ruland, J., additional, Beyer, M., additional, Greter, M., additional, Kopf, M., additional, Schultze, J.L., additional, and Schlitzer, A., additional
- Published
- 2022
- Full Text
- View/download PDF
6. Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells
- Author
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Bosurgi, L., Brunelli, S., Rigamonti, E., Monno, A., Manfredi, A. A., and Rovere-Querini, P.
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- 2015
- Full Text
- View/download PDF
7. Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients
- Author
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Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, Gnirck AC, Cortesi F, Schultheiß C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lütgehetmann M, Pfefferle S, Steurer S, Zur-Wiesch JS, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gaglian
- Published
- 2021
- Full Text
- View/download PDF
8. Redox remodeling: a candidate regulator of HMGB1 function in injured skeletal muscle
- Author
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Vezzoli M, Castellani P, Campana L, Coma G, Bosurgi L, MANFREDI , ANGELO ANDREA M. A., BIANCHI , MARCO EMILIO, Rubartelli A, ROVERE QUERINI , PATRIZIA, Vezzoli, M, Castellani, P, Campana, L, Coma, G, Bosurgi, L, Manfredi, ANGELO ANDREA M. A., Bianchi, MARCO EMILIO, Rubartelli, A, and ROVERE QUERINI, Patrizia
- Published
- 2010
9. Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells
- Author
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Bosurgi, L, Brunelli, S, Rigamonti, E, Monno, A, Manfredi, A, Rovere Querini, P, BRUNELLI, SILVIA, Rovere Querini, P., Bosurgi, L, Brunelli, S, Rigamonti, E, Monno, A, Manfredi, A, Rovere Querini, P, BRUNELLI, SILVIA, and Rovere Querini, P.
- Abstract
Summary: Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163+ infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies.
- Published
- 2015
10. Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells
- Author
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Bosurgi, L, primary, Brunelli, S, additional, Rigamonti, E, additional, Monno, A, additional, Manfredi, A A, additional, and Rovere-Querini, P, additional
- Published
- 2014
- Full Text
- View/download PDF
11. Transplanted mesoangioblasts require macrophage IL-10 for survival in a mouse model of muscle injury
- Author
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Bosurgi, L, Corna, G, Vezzoli, M, Touvier, T, Cossu, G, Manfredi, A, Brunelli, S, Rovere Querini, P, BRUNELLI, SILVIA, Rovere Querini, P., Bosurgi, L, Corna, G, Vezzoli, M, Touvier, T, Cossu, G, Manfredi, A, Brunelli, S, Rovere Querini, P, BRUNELLI, SILVIA, and Rovere Querini, P.
- Abstract
The aim of this study was to verify whether macrophages influence the fate of transplanted mesoangioblasts-vessel-associated myogenic precursors-in a model of sterile toxin-induced skeletal muscle injury. We have observed that in the absence of macrophages, transplanted mesoangioblasts do not yield novel fibers. Macrophages retrieved from skeletal muscles at various times after injury display features that resemble those of immunoregulatory macrophages. Indeed, they secrete IL-10 and express CD206 and CD163 membrane receptors and high amounts of arginase I. We have reconstituted the muscle-associated macrophage population by injecting polarized macrophages before mesoangioblast injection: alternatively activated, immunoregulatory macrophages only support mesoangioblast survival and function. This action depends on the secretion of IL-10 in the tissue. Our results reveal an unanticipated role for tissue macrophages in mesoangioblast function. Consequently, the treatment of muscle disorders with mesoangioblasts should take into consideration coexisting inflammatory pathways, whose activation may prove crucial for its success.
- Published
- 2012
12. High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle
- Author
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Vezzoli, M, Castellani, P, Corna, G, Castiglioni, A, Bosurgi, L, Monno, A, Brunelli, S, Manfredi, A, Rubartelli, A, Rovere Querini, P, Manfredi, AA, Rovere Querini, P., BRUNELLI, SILVIA, Vezzoli, M, Castellani, P, Corna, G, Castiglioni, A, Bosurgi, L, Monno, A, Brunelli, S, Manfredi, A, Rubartelli, A, Rovere Querini, P, Manfredi, AA, Rovere Querini, P., and BRUNELLI, SILVIA
- Abstract
High-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecules, favors tissue regeneration via recruitment and activation of leukocytes and stem cells. Here we demonstrate, in a model of acute sterile muscle injury, that regeneration is accompanied by active reactive oxygen species (ROS) production counterbalanced and overcome by the generation of antioxidant moieties. Mitochondria are initially responsible for ROS formation. However, they undergo rapid disruption with almost complete disappearance. Twenty-four hours after injury, we observed a strong induction of MURF1 and atrogin-1 ubiquitin ligases, key signals in activation of the proteasome system and induction of muscle atrophy. At later time points, ROS generation is maintained by nonmitochondrial sources. The antioxidant response occurs in both regenerating fibers and leukocytes that express high levels of free thiols and antioxidant enzymes, such as superoxide dismutase 1 (SOD1) and thioredoxin. HMGB1, a protein thiol, weakly expressed in healthy muscles, increases during regeneration in parallel with the antioxidant response in both fibers and leukocytes. A reduced environment may be important to maintain HMGB1 bioactivity. Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro. We propose that the early antioxidant response in regenerating muscle limits HMGB1 oxidation, thus allowing successful muscle regeneration.
- Published
- 2011
13. Polarization dictates iron handling by inflammatory and alternatively activated macrophages
- Author
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Corna, G., primary, Campana, L., additional, Pignatti, E., additional, Castiglioni, A., additional, Tagliafico, E., additional, Bosurgi, L., additional, Campanella, A., additional, Brunelli, S., additional, Manfredi, A. A., additional, Apostoli, P., additional, Silvestri, L., additional, Camaschella, C., additional, and Rovere-Querini, P., additional
- Published
- 2010
- Full Text
- View/download PDF
14. Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells
- Author
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Silvia Brunelli, Angelo A. Manfredi, Antonella Monno, Elena Rigamonti, Patrizia Rovere-Querini, Lidia Bosurgi, Bosurgi, L, Brunelli, S, Rigamonti, E, Monno, A, Manfredi, A, Rovere Querini, P, Manfredi, ANGELO ANDREA M. A., and ROVERE QUERINI, Patrizia
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Macrophage ,Immunology ,Population ,Apoptosis ,Inflammation ,Biology ,Immunophenotyping ,Myoblasts ,Mice ,Phagocytosis ,medicine ,Animals ,Immunology and Allergy ,Myocyte ,education ,Phagocytosi ,education.field_of_study ,Gene Expression Profiling ,Macrophages ,Apoptosi ,Skeletal muscle ,Macrophage Activation ,macrophages, vessel associated progenitors ,Cell biology ,Phenotype ,medicine.anatomical_structure ,Gene Expression Regulation ,Female ,Focus on Dying Autologous Cells as Instructors of the Immune System. Series Originators and Editors: Christian Berens and Martin Herrmann ,medicine.symptom ,Stem cell ,Wound healing ,CD163 - Abstract
Summary Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163+ infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies.
- Published
- 2014
15. Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury
- Author
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Gianfranca Corna, Patrizia Rovere-Querini, Silvia Brunelli, Thierry Touvier, Angelo A. Manfredi, Michela Vezzoli, Lidia Bosurgi, Giulio Cossu, Bosurgi, L, Corna, G, Vezzoli, M, Touvier, T, Cossu, G, Manfredi, A, Brunelli, S, Rovere Querini, P, Manfredi, ANGELO ANDREA M. A., and ROVERE QUERINI, Patrizia
- Subjects
Immunology ,Blotting, Western ,Muscle Fibers, Skeletal ,Fluorescent Antibody Technique ,Enzyme-Linked Immunosorbent Assay ,Cell Separation ,Muscle disorder ,Biology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Macrophage ,Animals ,Muscle, Skeletal ,030304 developmental biology ,0303 health sciences ,Mesoangioblast ,Reverse Transcriptase Polymerase Chain Reaction ,IL10, mesoangioblasts ,Macrophages ,Stem Cells ,Skeletal muscle ,Cell Differentiation ,Flow Cytometry ,Cell biology ,Interleukin-10 ,Arginase ,Mice, Inbred C57BL ,Interleukin 10 ,Disease Models, Animal ,medicine.anatomical_structure ,Female ,Stem cell ,Pericytes ,CD163 ,030217 neurology & neurosurgery ,Stem Cell Transplantation - Abstract
The aim of this study was to verify whether macrophages influence the fate of transplanted mesoangioblasts—vessel-associated myogenic precursors—in a model of sterile toxin-induced skeletal muscle injury. We have observed that in the absence of macrophages, transplanted mesoangioblasts do not yield novel fibers. Macrophages retrieved from skeletal muscles at various times after injury display features that resemble those of immunoregulatory macrophages. Indeed, they secrete IL-10 and express CD206 and CD163 membrane receptors and high amounts of arginase I. We have reconstituted the muscle-associated macrophage population by injecting polarized macrophages before mesoangioblast injection: alternatively activated, immunoregulatory macrophages only support mesoangioblast survival and function. This action depends on the secretion of IL-10 in the tissue. Our results reveal an unanticipated role for tissue macrophages in mesoangioblast function. Consequently, the treatment of muscle disorders with mesoangioblasts should take into consideration coexisting inflammatory pathways, whose activation may prove crucial for its success.
- Published
- 2012
- Full Text
- View/download PDF
16. High-Mobility Group Box 1 Release and Redox Regulation Accompany Regeneration and Remodeling of Skeletal Muscle
- Author
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Silvia Brunelli, Patrizia Castellani, Michela Vezzoli, Gianfranca Corna, Anna Rubartelli, Lidia Bosurgi, Patrizia Rovere-Querini, Alessandra Castiglioni, Angelo A. Manfredi, Antonella Monno, Vezzoli, M, Castellani, P, Corna, G, Castiglioni, A, Bosurgi, L, Monno, A, Brunelli, S, Manfredi, A, Rubartelli, A, Rovere Querini, P, Manfredi, ANGELO ANDREA M. A., and ROVERE QUERINI, Patrizia
- Subjects
Satellite Cells, Skeletal Muscle ,Physiology ,Ubiquitin-Protein Ligases ,Blotting, Western ,Clinical Biochemistry ,Antigens, Differentiation, Myelomonocytic ,Fluorescent Antibody Technique ,Muscle Proteins ,Biology ,HMGB1 ,Biochemistry ,Antioxidants ,Tripartite Motif Proteins ,Superoxide dismutase ,Mice ,Microscopy, Electron, Transmission ,Ubiquitin ,Antigens, CD ,medicine ,Animals ,Regeneration ,HMGB1 Protein ,Muscle, Skeletal ,Molecular Biology ,Cells, Cultured ,General Environmental Science ,chemistry.chemical_classification ,Reactive oxygen species ,SKP Cullin F-Box Protein Ligases ,Reverse Transcriptase Polymerase Chain Reaction ,Regeneration (biology) ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,Muscle atrophy ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,biology.protein ,General Earth and Planetary Sciences ,Female ,medicine.symptom ,Thioredoxin ,Reactive Oxygen Species ,Oxidation-Reduction - Abstract
High-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecules, favors tissue regeneration via recruitment and activation of leukocytes and stem cells. Here we demonstrate, in a model of acute sterile muscle injury, that regeneration is accompanied by active reactive oxygen species (ROS) production counterbalanced and overcome by the generation of antioxidant moieties. Mitochondria are initially responsible for ROS formation. However, they undergo rapid disruption with almost complete disappearance. Twenty-four hours after injury, we observed a strong induction of MURF1 and atrogin-1 ubiquitin ligases, key signals in activation of the proteasome system and induction of muscle atrophy. At later time points, ROS generation is maintained by nonmitochondrial sources. The antioxidant response occurs in both regenerating fibers and leukocytes that express high levels of free thiols and antioxidant enzymes, such as superoxide dismutase 1 (SOD1) and thioredoxin. HMGB1, a protein thiol, weakly expressed in healthy muscles, increases during regeneration in parallel with the antioxidant response in both fibers and leukocytes. A reduced environment may be important to maintain HMGB1 bioactivity. Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro. We propose that the early antioxidant response in regenerating muscle limits HMGB1 oxidation, thus allowing successful muscle regeneration.
- Published
- 2011
17. Subcapsular Sinus Macrophages Prevent CNS Invasion Upon Peripheral Infection With a Neurotropic Virus
- Author
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Sean P. J. Whelan, Luca G. Guidotti, Elena Tonti, Tobias Junt, Matteo Iannacone, Lidia Bosurgi, Sarah E. Henrickson, Ulrich H. von Andrian, E. Ashley Moseman, Iannacone, M, Moseman, Ea, Tonti, E, Bosurgi, L, Junt, T, Henrickson, Se, Whelan, Sp, Guidotti, Luca, and von Andrian, Uh
- Subjects
Nervous system ,viruses ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Mononegavirales ,Lymph node ,030304 developmental biology ,Neurotropic virus ,0303 health sciences ,Multidisciplinary ,biology ,integumentary system ,Rabies virus ,biology.organism_classification ,Virology ,3. Good health ,Lymphatic system ,medicine.anatomical_structure ,Vesicular stomatitis virus ,Immunology ,tissues ,030215 immunology - Abstract
Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7-10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.
- Published
- 2010
18. Macrophages in injured skeletal muscle: a perpetuum mobile causing and limiting fibrosis, prompting or restricting resolution and regeneration
- Author
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Lidia eBosurgi, Angelo A. Manfredi, Patrizia eRovere Querini, Bosurgi, L, Manfredi, ANGELO ANDREA M. A., and ROVERE QUERINI, Patrizia
- Subjects
lcsh:Immunologic diseases. Allergy ,Pathology ,medicine.medical_specialty ,Immunology ,Scars ,wound healing ,Review Article ,Fibrosis ,medicine ,Immunology and Allergy ,Progenitor cell ,skeletal muscle ,innate immunity ,alternative activation ,Innate immune system ,business.industry ,Regeneration (biology) ,Skeletal muscle ,medicine.disease ,Cell biology ,macrophages ,medicine.anatomical_structure ,medicine.symptom ,Stem cell ,lcsh:RC581-607 ,business ,Wound healing - Abstract
Macrophages are present in regenerating skeletal muscles and participate in the repair process. This is due to a unique feature of macrophages, i.e., their ability to perceive signals heralding ongoing tissue injury and to broadcast the news to cells suited at regenerating the tissue such as stem and progenitor cells. Macrophages play a complex role in the skeletal muscle, probably conveying information on the pattern of healing which is appropriate to ensure an effective healing of the tissue, yielding novel functional fibers. Conversely, they are likely to be involved in limiting the efficacy of regeneration, with formation of fibrotic scars and fat replacement of the tissue when the original insult persists. In this review we consider the beneficial versus the detrimental actions of macrophages during the response to muscle injury, with attention to the available information on the molecular code macrophages rely on to guide, throughout the various phases of muscle healing, the function of conventional and unconventional stem cells. Decrypting this code would represent a major step forward toward the establishment of novel targeted therapies for muscle diseases.
- Published
- 2011
19. Low hepcidin accounts for the proinflammatory status associated with iron deficiency
- Author
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Laura Silvestri, Clara Camaschella, Alessia Pagani, Antonella Nai, Gianfranca Corna, Patrizia Rovere-Querini, Lidia Bosurgi, Pagani, A, Nai, A, Corna, G, Bosurgi, L, ROVERE QUERINI, Patrizia, Camaschella, Clara, and Silvestri, L.
- Subjects
Lipopolysaccharides ,Male ,STAT3 Transcription Factor ,medicine.medical_specialty ,Lipopolysaccharide ,Iron ,Immunology ,Ferroportin ,Inflammation ,Smad Proteins ,Biochemistry ,Proinflammatory cytokine ,chemistry.chemical_compound ,Mice ,Hepcidins ,Hepcidin ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Interleukin 6 ,Acute-Phase Reaction ,Mice, Knockout ,biology ,Anemia, Iron-Deficiency ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Macrophages ,Serine Endopeptidases ,Membrane Proteins ,Cell Biology ,Hematology ,Iron deficiency ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Liver ,Bone Morphogenetic Proteins ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom ,Spleen ,Antimicrobial Cationic Peptides ,Signal Transduction - Abstract
Hepcidin is an antimicrobial peptide that controls systemic iron homeostasis. Hepcidin binding to its receptor ferroportin reduces iron availability, thus controlling microbial growth. In parallel it triggers an anti-inflammatory response in macrophages. Hepcidin is transcriptionally regulated by iron, through the bone morphogenetic protein–son of mothers against decapentaplegic (BMP-SMAD) pathway and by inflammation, through IL6-mediated STAT3 signaling. To investigate the mechanisms linking iron and inflammation, we treated C57BL/6 iron-deficient mice with a sublethal dose of lipopolysaccharide (LPS) and analyzed their inflammatory response in comparison with controls. We show that iron-deprived mice have a proinflammatory condition, exacerbated by LPS treatment leading to increased IL6 and TNFα mRNA in liver and spleen macrophages, and increased serum IL6 (482.29 ± 205.59 pg/mL) versus controls (69.01 ± 17.52 pg/mL; P < .05). Hepcidin was undetectable in iron-deficient mice but pretreatment with hepcidin normalized their response to LPS. Tmprss6−/− mice, characterized by iron deficiency and high hepcidin, show a blunted inflammatory response when challenged with LPS. Our data support a model in which the lack of hepcidin is responsible of the high inflammatory response to LPS in iron deficiency. The proinflammatory status associated with chronic iron deficiency could explain the resistance to infection seen in this condition.
- Published
- 2011
20. Polarization dictates iron handling by inflammatory and alternatively activated macrophages
- Author
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Alessandra Castiglioni, Gianfranca Corna, Laura Silvestri, Angelo A. Manfredi, Alessandro Campanella, Lara Campana, Silvia Brunelli, Pietro Apostoli, Clara Camaschella, Patrizia Rovere-Querini, Enrico Tagliafico, Lidia Bosurgi, Emanuele Pignatti, Corna, G, Campana, L, Pignatti, E, Castiglioni, A, Tagliafico, E, Bosurgi, L, Campanella, A, Brunelli, S, Manfredi, ANGELO ANDREA M. A., Apostoli, P, Silvestri, L, Camaschella, Clara, ROVERE QUERINI, Patrizia, Manfredi, A, Camaschella, C, and Rovere Querini, P
- Subjects
Macrophage ,Apoferritin ,Iron ,media_common.quotation_subject ,Macrophage-activating factor ,Ferroportin ,Macrophage polarization ,Transferrin receptor ,Inflammation ,Lymphocyte Activation ,Interferon-gamma ,Mice ,Receptors, Transferrin ,medicine ,Iron Regulatory Protein 1 ,Internalization ,Iron Regulatory Protein 2 ,gene expression profiling microarrays iron handling inflammation macrophages ,Interleukin 4 ,media_common ,biology ,Animal ,Hematology ,Macrophage Activation ,Cell biology ,T-Lymphocyte ,Gene Expression Regulation ,Cation Transport Protein ,Biochemistry ,biology.protein ,Original Article ,Interleukin-4 ,medicine.symptom ,Intracellular - Abstract
Background Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes. Design and Methods Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells. Results M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize - albeit with low efficiency - iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferring receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective. Conclusions Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2). © 2010 Ferrata Storti Foundation.
- Published
- 2010
21. Requirement of HMGB1 for stromal cell-derived factor-1/CXCL12-dependent migration of macrophages and dendritic cells
- Author
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Lidia Bosurgi, Patrizia Rovere-Querini, Angelo A. Manfredi, Lara Campana, Marco Bianchi, Campana, L, Bosurgi, L, Bianchi, MARCO EMILIO, Manfredi, ANGELO ANDREA M. A., and ROVERE QUERINI, Patrizia
- Subjects
Chemokine ,Stromal cell ,Immunology ,Motility ,chemical and pharmacologic phenomena ,Inflammation ,Bone Marrow Cells ,Mice ,Immune system ,Cell Movement ,medicine ,Lymph node stromal cell ,Immunology and Allergy ,Animals ,Stromal cell-derived factor 1 ,HMGB1 Protein ,Cells, Cultured ,biology ,Chemotaxis ,Macrophages ,Cell Biology ,Dendritic Cells ,Chemokine CXCL12 ,Cell biology ,Mice, Inbred C57BL ,biology.protein ,Female ,medicine.symptom ,Stromal Cells - Abstract
Alterations in the capability of CF lung macrophage to respond and clear airway pathogens might contribute to the development of lung disease in cystic fibrosis. HMGB1 finely tunes the function of DCs, thus influencing their maturation program and eventually the establishment of adaptive, T cell–dependent immune responses. Moreover, it promotes the up–regulation of receptors for lymph node chemokines, regulates the remodeling of the cytoskeleton of migrating cells, and sustains their journey to secondary lymphoid organs via a RAGE–dependent pathway. The inflammatory properties of HMGB1 depend at least partially on the ability to complex with soluble moieties, including nucleic acids, microbial products, and cytokines. Here, we show that bone marrow–derived mouse DCs release HMGB1 during CXCL12–dependent migration in vitro. Macrophages share this property, suggesting that it may be a general feature of CXCL12–responsive leukocytes. The chemotactic response to rCXCL12 of DCs and macrophages abates in the presence of the HMGB1 antagonist BoxA. HMGB1 secreted from DCs and macrophages binds to CXCL12 in the fluid phase and protects the chemokine conformation and function in a reducing environment. Altogether, our data indicate that HMGB1 release is required for CXCL12 ability to attract myeloid–derived cells and reveal a functional interaction between the two molecules that possibly contributes to the regulation of leukocyte recruitment and motility.
- Published
- 2009
22. Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways
- Author
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Rossana Tonlorenzi, Marco Bianchi, Patrizia Rovere-Querini, Silvia Brunelli, Karine Lolmede, Emilio Clementi, Lara Campana, Michela Vezzoli, Giulio Cossu, Angelo A. Manfredi, Lidia Bosurgi, Lolmede, K, Campana, L, Vezzoli, M, Bosurgi, L, Tonlorenzi, R, Clementi, E, Bianchi, M, Cossu, G, Manfredi, A, Brunelli, S, Rovere Querini, P, Bianchi, MARCO EMILIO, Manfredi, ANGELO ANDREA M. A., and ROVERE QUERINI, Patrizia
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Vascular Endothelial Growth Factor A ,Immunology ,Inflammation ,HMGB1 ,Cell Movement ,macrophages, mesoangioblast ,medicine ,Immunology and Allergy ,Macrophage ,Humans ,Interleukin 8 ,HMGB1 Protein ,Muscle, Skeletal ,Cells, Cultured ,Mesoangioblast ,biology ,Tumor Necrosis Factor-alpha ,Chemotaxis ,Macrophages ,Stem Cells ,Cell Biology ,Macrophage Activation ,Cell biology ,Vascular endothelial growth factor A ,Matrix Metalloproteinase 9 ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom ,Stem cell - Abstract
Inflammatory macrophages recruited at the site of damaged muscles progressively acquire an alternative activation profile. Inflammatory (M1) and alternatively activated (M2) macrophages exert various and even opposite functions. M1 cells amplify tissue damage, and M2 cells dispose of necrotic fibers and deliver survival signals to myogenic precursors, finally supporting healing. A critical step in muscle healing is the recruitment of myogenic stem cells, including vessel-associated stem cells (mesoangioblasts), which have been demonstrated to home to damaged skeletal muscle selectively and preferentially. Little information is available about the signals involved and the role played by infiltrating macrophages. Here, we report that the polarization of macrophages dramatically skews the secretion of high mobility group box 1 (HMGB1), TNF-α, vascular endothelial growth factor, and metalloproteinase 9 (MMP-9), molecules involved in the regulation of cell diapedesis and migration. All polarized macrophage populations were strikingly effective at inducing mesoangioblast migration. By means of specific inhibitors, we verified that the recruitment of mesoangioblasts requires the secretion of HMGB1 and TNF-α by M1 cells and of MMP-9 by M2 cells. Together, these data demonstrate a feature, unrecognized previously, of macrophages: their ability to attract stem cells, which is conserved throughout their polarization. Moreover, they open the possibility of novel strategies, aimed at interfering selectively with signals that recruit blood-derived stem cells toward pro- or anti-inflammatory macrophages.
- Published
- 2009
23. HMGB1: a two-headed signal regulating tumor progression and immunity
- Author
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Lara Campana, Lidia Bosurgi, Patrizia Rovere-Querini, Campana, L, Bosurgi, L, and ROVERE QUERINI, Patrizia
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Toll-like receptor ,Innate immune system ,biology ,Immunology ,Receptor for Advanced Glycation End Products ,Toll-Like Receptors ,Immunity ,chemical and pharmacologic phenomena ,Apoptosis ,HMGB1 ,Tumor progression ,Neoplasms ,biology.protein ,TLR4 ,Immunology and Allergy ,Animals ,Humans ,HMGB1 Protein ,Receptors, Immunologic ,Receptor ,Neuroscience ,Intracellular - Abstract
Cells of the innate immune system sense tissue damage recognizing in the extracellular environment bona fide intracellular moieties, like high mobility group box 1 (HMGB1). In the case of tumors, HMGB1 recognition has a paradoxical dual effect: it promotes tumor neoangiogenesis and triggers protective anti-neoplastic T-cell responses. Recent advances in the study of HMGB1 have identified candidate molecular mechanisms underlying these apparently contrasting outcomes. A surprising role for innate receptors, including toll like receptor 4 (TLR4), in the response to conventional cancer radio and chemotherapy has also recently emerged, providing new insight into the mechanisms by which these treatments actually work.
- Published
- 2008
24. B Cell Maintenance of Subcapsular Sinus Macrophages Protects against a Fatal Viral Infection Independent of Adaptive Immunity
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Nir Hacohen, Elena Tonti, Lidia Bosurgi, Nicolas Chevrier, E. Ashley Moseman, Ulrich H. von Andrian, Alexei V. Tumanov, Matteo Iannacone, Yang Xin Fu, Moseman, Ea, Iannacone, M, Bosurgi, L, Tonti, E, Chevrier, N, Tumanov, A, Fu, Yx, Hacohen, N, and von Andrian, Uh
- Subjects
viruses ,Immunology ,Adaptive Immunity ,Antibodies, Viral ,Article ,Virus ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,medicine ,Animals ,Immunology and Allergy ,Macrophage ,Neutralizing antibody ,B cell ,030304 developmental biology ,Mice, Knockout ,B-Lymphocytes ,Mice, Inbred BALB C ,0303 health sciences ,biology ,Macrophages ,Lymphotoxin alpha1, beta2 Heterotrimer ,Vesiculovirus ,biology.organism_classification ,Acquired immune system ,Antibodies, Neutralizing ,Virology ,Immunity, Innate ,3. Good health ,Mice, Inbred C57BL ,Infectious Diseases ,medicine.anatomical_structure ,Vesicular stomatitis virus ,Interferon Type I ,biology.protein ,Lymph Nodes ,Antibody ,Vesicular Stomatitis ,Signal Transduction ,030215 immunology - Abstract
Neutralizing antibodies have been thought to be required for protection against acutely cytopathic viruses, such as the neurotropic vesicular stomatitis virus (VSV). Utilizing mice that possess B cells but lack antibodies, we show here that survival upon subcutaneous (s.c.) VSV challenge was independent of neutralizing antibody production or cell-mediated adaptive immunity. However, B cells were absolutely required to provide lymphotoxin (LT) alpha 1 beta 2, which maintained a protective subcapsular sinus (SCS) macrophage phenotype within virus draining lymph nodes (LNs). Macrophages within the SCS of B cell-deficient LNs, or of mice that lack LT alpha 1 beta 2 selectively in B cells, displayed an aberrant phenotype, failed to replicate VSV, and therefore did not produce type I interferons, which were required to prevent fatal VSV invasion of intranodal nerves. Thus, although B cells are essential for survival during VSV infection, their contribution involves the provision of innate differentiation and maintenance signals to macrophages, rather than adaptive immune mechanisms.
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25. Harnessing apoptotic cells to enhance efficiency of macrophage-based cell therapy.
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Liebold I and Bosurgi L
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- Humans, Apoptosis, Macrophages metabolism, Cell- and Tissue-Based Therapy methods
- Published
- 2024
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26. Women in STEM becoming independent: Our shared motivation and enthusiasm are our driving force.
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Andreeva L, Bosurgi L, Chong SZ, Chu C, Ge Y, Hoste E, Jurado KA, Lengefeld J, Mishra A, Wculek S, and Young A
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- Humans, Female, Science, Motivation
- Published
- 2024
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27. Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages.
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Liebold I, Al Jawazneh A, Casar C, Lanzloth C, Leyk S, Hamley M, Wong MN, Kylies D, Gräfe SK, Edenhofer I, Aranda-Pardos I, Kriwet M, Haas H, Krause J, Hadjilaou A, Schromm AB, Richardt U, Eggert P, Tappe D, Weidemann SA, Ghosh S, Krebs CF, A-Gonzalez N, Worthmann A, Lohse AW, Huber S, Rothlin CV, Puelles VG, Jacobs T, Gagliani N, and Bosurgi L
- Subjects
- Animals, Mice, Hepatocytes immunology, Mice, Knockout, Neutrophils immunology, Disease Models, Animal, Apoptosis immunology, Interleukin-4 genetics, Interleukin-4 metabolism, Macrophages immunology, Phagocytosis immunology, Schistosomiasis mansoni genetics, Schistosomiasis mansoni immunology
- Abstract
Macrophages are functionally heterogeneous cells essential for apoptotic cell clearance. Apoptotic cells are defined by homogeneous characteristics, ignoring their original cell lineage identity. We found that in an interleukin-4 (IL-4)-enriched environment, the sensing of apoptotic neutrophils by macrophages triggered their tissue remodeling signature. Engulfment of apoptotic hepatocytes promoted a tolerogenic phenotype, whereas phagocytosis of T cells had little effect on IL-4-induced gene expression. In a mouse model of parasite-induced pathology, the transfer of macrophages conditioned with IL-4 and apoptotic neutrophils promoted parasitic egg clearance. Knockout of phagocytic receptors required for the uptake of apoptotic neutrophils and partially T cells, but not hepatocytes, exacerbated helminth infection. These findings suggest that the identity of apoptotic cells may contribute to the development of distinct IL-4-driven immune programs in macrophages.
- Published
- 2024
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28. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.
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Shiri AM, Zhang T, Bedke T, Zazara DE, Zhao L, Lücke J, Sabihi M, Fazio A, Zhang S, Tauriello DVF, Batlle E, Steglich B, Kempski J, Agalioti T, Nawrocki M, Xu Y, Riecken K, Liebold I, Brockmann L, Konczalla L, Bosurgi L, Mercanoglu B, Seeger P, Küsters N, Lykoudis PM, Heumann A, Arck PC, Fehse B, Busch P, Grotelüschen R, Mann O, Izbicki JR, Hackert T, Flavell RA, Gagliani N, Giannou AD, and Huber S
- Subjects
- Animals, Humans, Mice, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Interleukin-10, Receptors, Interleukin-10, Tumor Microenvironment, Colorectal Neoplasms, Liver Neoplasms pathology
- Abstract
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo., Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10., Results: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions., Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases., Impact and Implications: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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29. SARS-CoV-2 vaccination may mitigate dysregulation of IL-1/IL-18 and gastrointestinal symptoms of the post-COVID-19 condition.
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Fischer C, Willscher E, Paschold L, Gottschick C, Klee B, Diexer S, Bosurgi L, Dutzmann J, Sedding D, Frese T, Girndt M, Hoell JI, Gekle M, Addo MM, Schulze Zur Wiesch J, Mikolajczyk R, Binder M, and Schultheiß C
- Abstract
The rapid development of safe and effective vaccines helped to prevent severe disease courses after SARS-CoV-2 infection and to mitigate the progression of the COVID-19 pandemic. While there is evidence that vaccination may reduce the risk of developing post-COVID-19 conditions (PCC), this effect may depend on the viral variant. Therapeutic effects of post-infection vaccination have been discussed but the data for individuals with PCC remains inconclusive. In addition, extremely rare side effects after SARS-CoV-2 vaccination may resemble the heterogeneous PCC phenotype. Here, we analyze the plasma levels of 25 cytokines and SARS-CoV-2 directed antibodies in 540 individuals with or without PCC relative to one or two mRNA-based COVID-19 vaccinations as well as in 20 uninfected individuals one month after their initial mRNA-based COVID-19 vaccination. While none of the SARS-CoV-2 naïve individuals reported any persisting sequelae or exhibited PCC-like dysregulation of plasma cytokines, we detected lower levels of IL-1β and IL-18 in patients with ongoing PCC who received one or two vaccinations at a median of six months after infection as compared to unvaccinated PCC patients. This reduction correlated with less frequent reporting of persisting gastrointestinal symptoms. These data suggest that post-infection vaccination in patients with PCC might be beneficial in a subgroup of individuals displaying gastrointestinal symptoms., (© 2024. The Author(s).)
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- 2024
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30. Nmes1 is a novel regulator of mucosal response influencing intestinal healing potential.
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Hamley M, Leyk S, Casar C, Liebold I, Jawazneh AA, Lanzloth C, Böttcher M, Haas H, Richardt U, Rothlin CV, Jacobs T, Huber S, Adlung L, Pelczar P, Henao-Mejia J, and Bosurgi L
- Subjects
- Animals, Mice, Cytokines, Intestines, Wound Healing, Colitis drug therapy, Intestinal Mucosa
- Abstract
The initiation of tissue remodeling following damage is a critical step in preventing the development of immune-mediated diseases. Several factors contribute to mucosal healing, leading to innovative therapeutic approaches for managing intestinal disorders. However, uncovering alternative targets and gaining mechanistic insights are imperative to enhance therapy efficacy and broaden its applicability across different intestinal diseases. Here we demonstrate that Nmes1, encoding for Normal Mucosa of Esophagus-Specific gene 1, also known as Aa467197, is a novel regulator of mucosal healing. Nmes1 influences the macrophage response to the tissue remodeling cytokine IL-4 in vitro. In addition, using two murine models of intestinal damage, each characterized by a type 2-dominated environment with contrasting functions, the ablation of Nmes1 results in decreased intestinal regeneration during the recovery phase of colitis, while enhancing parasitic egg clearance and reducing fibrosis during the advanced stages of Schistosoma mansoni infection. These outcomes are associated with alterations in CX3CR1
+ macrophages, cells known for their wound-healing potential in the inflamed colon, hence promising candidates for cell therapies. All in all, our data indicate Nmes1 as a novel contributor to mucosal healing, setting the basis for further investigation into its potential as a new target for the treatment of colon-associated inflammation., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)- Published
- 2024
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31. Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility.
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Dörk R, Pelczar P, Shiri AM, Volmari A, Zierz E, Giannou A, Böttcher M, Bosurgi L, Huber S, and Manthey CF
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- Mice, Animals, Myeloid Cells pathology, Anti-Inflammatory Agents adverse effects, Dextran Sulfate, Disease Models, Animal, Mice, Inbred C57BL, Gastrointestinal Microbiome, Colitis pathology, Inflammatory Bowel Diseases complications
- Abstract
Background and Aims: The incidence of inflammatory bowel diseases [IBD] is steadily increasing, and thus the identification of new targets to improve therapy is a major goal. Growth factors of the PDGF family and their receptors are expressed early in intestinal development and are found in mononuclear cells and macrophages in adult tissues. Macrophages play a distinct role in the pathogenesis of IBD since their function is crucial to maintaining tolerance., Methods: We aimed to study the role of myeloid expression of PDGFR-α in mediating intestinal homeostasis in mouse IBD and infectious models., Results: Our results show that loss of myeloid PDGFR-α increases susceptibility to dextran saline sulphate-induced colitis. Accordingly, LysM-PDGFR-α-/- mice showed higher colitis scores, and reduced levels of anti-inflammatory macrophages compared to control mice. This effect was mediated via a pro-colitogenic microbiota, which developed in the absence of myeloid PDGFR-α and caused increased colitis susceptibility in gnotobiotic mice upon faecal microbiota transplantation compared to controls. Furthermore, LysM-PDGFR-α-/- mice had a leaky gut, accompanied by impaired phagocytosis, resulting in a severe barrier defect., Conclusions: Taken together, our results indicate a protective role for myeloid PDGFR-α in maintaining gut homeostasis by promoting a protective intestinal microbiota and providing an anti-inflammatory macrophage phenotype., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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32. Enabling X-ray fluorescence imaging for in vivo immune cell tracking.
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Staufer T, Körnig C, Liu B, Liu Y, Lanzloth C, Schmutzler O, Bedke T, Machicote A, Parak WJ, Feliu N, Bosurgi L, Huber S, and Grüner F
- Subjects
- Animals, Mice, X-Rays, Radiography, Optical Imaging, Tomography, X-Ray Computed methods, Cell Tracking
- Abstract
The infiltration of immune cells into sites of inflammation is one key feature of immune mediated inflammatory diseases. A detailed assessment of the in vivo dynamics of relevant cell subtypes could booster the understanding of this disease and the development of novel therapies. We show in detail how advanced X-ray fluorescence imaging enables such quantitative in vivo cell tracking, offering solutions that could pave the way beyond what other imaging modalities provide today. The key for this achievement is a detailed study of the spectral background contribution from multiple Compton scattering in a mouse-scaled object when this is scanned with a monochromatic pencil X-ray beam from a synchrotron. Under optimal conditions, the detection sensitivity is sufficient for detecting local accumulations of the labelled immune cells, hence providing experimental demonstration of in vivo immune cell tracking in mice., (© 2023. The Author(s).)
- Published
- 2023
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33. TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD.
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Liebold I, Meyer S, Heine M, Kuhl A, Witt J, Eissing L, Fischer AW, Koop AC, Kluwe J, Wiesch JSZ, Wehmeyer M, Knippschild U, Scheja L, Heeren J, Bosurgi L, and Worthmann A
- Subjects
- Humans, Mice, Animals, Liver Cirrhosis pathology, Macrophages metabolism, Apoptosis, Membrane Glycoproteins genetics, Receptors, Immunologic, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2
+ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro . Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro , which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2+ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis.- Published
- 2023
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34. Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19.
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Schultheiß C, Willscher E, Paschold L, Gottschick C, Klee B, Bosurgi L, Dutzmann J, Sedding D, Frese T, Girndt M, Höll JI, Gekle M, Mikolajczyk R, and Binder M
- Subjects
- Humans, Biomarkers, Cohort Studies, COVID-19 complications, Disease Progression, Quality of Life, SARS-CoV-2, Macrophages metabolism, Post-Acute COVID-19 Syndrome diagnosis, Post-Acute COVID-19 Syndrome metabolism, Spike Glycoprotein, Coronavirus blood, Spike Glycoprotein, Coronavirus chemistry
- Abstract
Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair the quality of life. Underlying mechanisms ranging from persistent viruses to innate and adaptive immune dysregulation have been discussed. Here, we profiled the plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero), including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as a potential biomarker for persistent viral reservoirs. At a median time of 8 months after infection, we found pronounced dysregulation in almost all tested soluble factors, including both pro-inflammatory and pro-fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC-specific patterns involving CCL2/MCP-1 and IL-8 that either correlated with sCD162, sCD206/MMR, IFN-α2, IL-17A and IL-33, or IL-18 and IL-23. None of the analyzed factors correlated with the detectability or levels of circulating S1, indicating that this represents an independent subset of patients with PASC. These data confirm prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrate its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)
- Published
- 2023
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35. The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19.
- Author
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Schultheiß C, Willscher E, Paschold L, Gottschick C, Klee B, Henkes SS, Bosurgi L, Dutzmann J, Sedding D, Frese T, Girndt M, Höll JI, Gekle M, Mikolajczyk R, and Binder M
- Subjects
- Cohort Studies, Disease Progression, Humans, Immunologic Tests, Interleukin-1beta immunology, Interleukin-6 immunology, Tumor Necrosis Factor-alpha immunology, Post-Acute COVID-19 Syndrome, COVID-19 complications, COVID-19 immunology, COVID-19 pathology, Cytokines immunology
- Abstract
Post-acute sequelae of COVID-19 (PASC) is emerging as global problem with unknown molecular drivers. Using a digital epidemiology approach, we recruited 8,077 individuals to the cohort study for digital health research in Germany (DigiHero) to respond to a basic questionnaire followed by a PASC-focused survey and blood sampling. We report the first 318 participants, the majority thereof after mild infections. Of those, 67.8% report PASC, predominantly consisting of fatigue, dyspnea, and concentration deficit, which persists in 60% over the mean 8-month follow-up period and resolves independently of post-infection vaccination. PASC is not associated with autoantibodies, but with elevated IL-1β, IL-6, and TNF plasma levels, which we confirm in a validation cohort with 333 additional participants and a longer time from infection of 10 months. Blood profiling and single-cell data from early infection suggest the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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36. Apoptotic cell signals and heterogeneity in macrophage function: Fine-tuning for a healthy liver.
- Author
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Liebold I, Jawazneh AA, Hamley M, and Bosurgi L
- Subjects
- Genetic Heterogeneity, Humans, Signal Transduction, Apoptosis physiology, Liver physiology, Macrophages physiology
- Abstract
Functional heterogeneity in tissue macrophage populations has often been traced to developmental and spatial cues. Upon tissue damage, macrophages are exposed to soluble mediators secreted by activated cells, which shape their polarisation. Interestingly, macrophages are concomitantly exposed to a variety of different dying cells, which carry miscellaneous signals and that need to be recognised and promptly up-taken by professional phagocytes. This review discusses how differences in the nature of the dying cells, like their morphological and biochemical features as well as the specificity of phagocytic receptor usage on macrophages, might contribute to the transcriptional and functional heterogeneity observed in phagocytic cells in the tissue., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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37. Efferocytosis fuels malignant pleural effusion through TIMP1.
- Author
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Zhao L, Giannou AD, Xu Y, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L, Huber S, and Gagliani N
- Abstract
Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of Axl and Mertk in Mφs or IL-10 receptor in DCs or Timp1 substantially reduced MPE progression. Our results delineate an inflammatory cascade-from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs-that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2021
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38. Management of cell death in parasitic infections.
- Author
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Bosurgi L and Rothlin CV
- Subjects
- Animals, Apoptosis, Humans, Macrophages, Phosphatidylserines, Parasites, Parasitic Diseases
- Abstract
For a long time, host cell death during parasitic infection has been considered a reflection of tissue damage, and often associated with disease pathogenesis. However, during their evolution, protozoan and helminth parasites have developed strategies to interfere with cell death so as to spread and survive in the infected host, thereby ascribing a more intriguing role to infection-associated cell death. In this review, we examine the mechanisms used by intracellular and extracellular parasites to respectively inhibit or trigger programmed cell death. We further dissect the role of the prototypical "eat-me signal" phosphatidylserine (PtdSer) which, by being exposed on the cell surface of damaged host cells as well as on some viable parasites via a process of apoptotic mimicry, leads to their recognition and up-take by the neighboring phagocytes. Although barely dissected so far, the engagement of different PtdSer receptors on macrophages, by shaping the host immune response, affects the overall infection outcome in models of both protozoan and helminth infections. In this scenario, further understanding of the molecular and cellular regulation of the PtdSer exposing cell-macrophage interaction might allow the identification of new therapeutic targets for the management of parasitic infection., (© 2021. The Author(s).)
- Published
- 2021
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39. Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4 + T Effector and Regulatory T Cells in Cutaneous Leishmaniasis.
- Author
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de Freitas E Silva R, Gálvez RI, Pereira VRA, de Brito MEF, Choy SL, Lotter H, Bosurgi L, and Jacobs T
- Subjects
- Adolescent, Adult, Animals, B7-H1 Antigen metabolism, CD4-Positive T-Lymphocytes metabolism, Cytokines metabolism, Female, Humans, Inflammation, Leishmania, Leishmaniasis, Cutaneous blood, Leishmaniasis, Cutaneous pathology, Lymph Nodes immunology, Macrophages immunology, Macrophages metabolism, Male, Mice, Middle Aged, Monocytes immunology, Monocytes metabolism, Phenotype, Programmed Cell Death 1 Receptor metabolism, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Young Adult, B7-H1 Antigen immunology, CD4-Positive T-Lymphocytes immunology, Leishmaniasis, Cutaneous immunology, Programmed Cell Death 1 Receptor immunology, T-Lymphocyte Subsets immunology
- Abstract
Cutaneous Leishmaniasis (CL) affects up to one million people every year and treatments are costly and toxic. The regulation of the host immune response is complex and the knowledge of how CD4
+ T cells are activated and maintained during Leishmania infection is still limited. Current therapies aim to target programmed cell death (PD)-1 and programmed cell death ligand (PD-L)-1 in order to boost T cell activity. However, the role of the PD-1/PD-L1 axis during Leishmania infection is still unclear. In this study, we found that patients with active and post-treatment CL displayed different subsets of CD4+ PD-1+ T cells. Accordingly, L. major- infected mice upregulated PD-1 on activated CD4+ T effector cells and PD-L1 on resident macrophages and infiltrating monocytes at the site of infection. L. major- infected Pdl1-/- mice expressed lower levels of MHCII and higher levels of CD206 on macrophages and monocytes and, more importantly, the lack of PD-L1 contributed to a reduced frequency of CD4+ Ly6Chi T effector cells and an increase of CD4+ Foxp3+ regulatory T cells at the site of infection and in draining lymph nodes. Additionally, the lack of PD-L1 was associated with lower production of IL-27 by infiltrating monocytes and lower levels of the Th1 cytokines IFN-γ and TNF-α produced by CD4+ T effector cells. Pdl1-/- mice initially exhibited larger lesions despite having a similar parasite load. Our results describe for the first time how the interruption of the PD-1/PD-L1 axis influences the immune response against CL and suggests that this axis regulates the balance between CD4+ Ly6Chi T effector cells and CD4+ Foxp3+ regulatory T cells., (Copyright © 2020 Freitas e Silva, Gálvez, Pereira, de Brito, Choy, Lotter, Bosurgi and Jacobs.)- Published
- 2020
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40. HVEM and CD160: Regulators of Immunopathology During Malaria Blood-Stage.
- Author
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Muscate F, Stetter N, Schramm C, Schulze Zur Wiesch J, Bosurgi L, and Jacobs T
- Subjects
- Adult, Aged, Animals, Cell Proliferation physiology, Cells, Cultured, GPI-Linked Proteins metabolism, Humans, Lymphocyte Activation physiology, Malaria, Cerebral parasitology, Mice, Mice, Inbred C57BL, Middle Aged, Plasmodium berghei metabolism, Plasmodium falciparum metabolism, Antigens, CD metabolism, CD8-Positive T-Lymphocytes metabolism, Malaria, Cerebral metabolism, Receptors, Immunologic metabolism, Receptors, Tumor Necrosis Factor, Member 14 metabolism
- Abstract
CD8
+ T cells are key players during infection with the malaria parasite Plasmodium berghei ANKA (PbA). While they cannot provide protection against blood-stage parasites, they can cause immunopathology, thus leading to the severe manifestation of cerebral malaria. Hence, the tight control of CD8+ T cell function is key in order to prevent fatal outcomes. One major mechanism to control CD8+ T cell activation, proliferation and effector function is the integration of co-inhibitory and co-stimulatory signals. In this study, we show that one such pathway, the HVEM-CD160 axis, significantly impacts CD8+ T cell regulation and thereby the incidence of cerebral malaria. Here, we show that the co-stimulatory molecule HVEM is indeed required to maintain CD8+ T effector populations during infection. Additionally, by generating a CD160-/- mouse line, we observe that the HVEM ligand CD160 counterbalances stimulatory signals in highly activated and cytotoxic CD8+ T effector cells, thereby restricting immunopathology. Importantly, CD160 is also induced on cytotoxic CD8+ T cells during acute Plasmodium falciparum malaria in humans. In conclusion, CD160 is specifically expressed on highly activated CD8+ T effector cells that are harmful during the blood-stage of malaria.- Published
- 2018
- Full Text
- View/download PDF
41. Chronicles of Cell Death Foretold: Specificities in the Mechanism of Disposal.
- Author
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Hughes LD, Bosurgi L, Ghosh S, and Rothlin CV
- Abstract
Massive turnover of cells occurs through apoptosis during the constant remodeling of our tissues at homeostasis, from the shedding of cells at exposed barrier surfaces to the elimination of autoreactive lymphocytes. However, a surge of apoptotic cells also accompanies tissue damage, infection, and inflammation. A salient feature of apoptosis in either scenario is the exposure of phosphatidylserine (PtdSer) on the outer leaflet of the plasma membrane. In response to this cue, a range of phagocytes are charged with the sizeable task of engulfing apoptotic bodies and disposing of the billions of cells that perish each day. The presence of apoptotic cells in the remarkably distinct immunological settings described above, therefore, raises the question of how phagocytes are able to coordinate appropriate responses to apoptotic cells-from their silent removal to the production of growth factors or tissue repair molecules-following such a ubiquitous signal as PtdSer exposure. Here, we consider several emergent properties of phagocytes and apoptotic cell clearance that may facilitate specification among this suite of potential responses.
- Published
- 2017
- Full Text
- View/download PDF
42. Death begets a new beginning.
- Author
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Bosurgi L, Hughes LD, Rothlin CV, and Ghosh S
- Subjects
- Animals, Cellular Microenvironment, Homeostasis, Humans, Wound Healing, Cell Death, Infections immunology, Inflammation immunology, Phagocytes physiology, Phagocytosis
- Abstract
Cell death is a perpetual feature of tissue microenvironments; each day under homeostatic conditions, billions of cells die and must be swiftly cleared by phagocytes. However, cell death is not limited to this natural turnover-apoptotic cell death can be induced by infection, inflammation, or severe tissue injury. Phagocytosis of apoptotic cells is thus coupled to specific functions, from the induction of growth factors that can stimulate the replacement of dead cells to the promotion of tissue repair or tissue remodeling in the affected site. In this review, we outline the mechanisms by which phagocytes sense apoptotic cell death and discuss how phagocytosis is integrated with environmental cues to drive appropriate responses., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
43. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells.
- Author
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Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, Gagliani N, Craft JE, Flavell RA, Ghosh S, and Rothlin CV
- Subjects
- Animals, Apoptosis, Inflammation chemically induced, Inflammation pathology, Mice, Strongylida Infections immunology, Thioglycolates, Interleukin-13 immunology, Interleukin-4 immunology, Macrophages immunology, Nippostrongylus physiology, Regeneration
- Abstract
Tissue repair is a subset of a broad repertoire of interleukin-4 (IL-4)- and IL-13-dependent host responses during helminth infection. Here we show that IL-4 or IL-13 alone was not sufficient, but IL-4 or IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis. By contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor, cell adhesion, or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines such as IL-4 or IL-13., (Copyright © 2017, American Association for the Advancement of Science.)
- Published
- 2017
- Full Text
- View/download PDF
44. IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge.
- Author
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Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, and Dixit VD
- Subjects
- Adipose Tissue immunology, Adipose Tissue metabolism, Adiposity, Animals, Cell Differentiation immunology, Diet, High-Fat, Insulin Resistance immunology, Insulin-Like Growth Factor I immunology, Interleukin-4 immunology, Macrophages metabolism, Mice, Mice, Knockout, Nippostrongylus pathogenicity, Phagocytosis genetics, Signal Transduction immunology, Strongylida Infections metabolism, Strongylida Infections parasitology, Insulin Resistance genetics, Insulin-Like Growth Factor I genetics, Macrophages immunology, Strongylida Infections immunology
- Abstract
In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
45. AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity.
- Author
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Schmid ET, Pang IK, Carrera Silva EA, Bosurgi L, Miner JJ, Diamond MS, Iwasaki A, and Rothlin CV
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Interferon Type I metabolism, Mice, Inbred C57BL, Mice, Knockout, Orthomyxoviridae Infections immunology, West Nile Fever immunology, Axl Receptor Tyrosine Kinase, Influenza A virus immunology, Lymphocyte Activation, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism, T-Lymphocytes immunology, West Nile virus immunology
- Abstract
The receptor tyrosine kinase (RTK) AXL is induced in response to type I interferons (IFNs) and limits their production through a negative feedback loop. Enhanced production of type I IFNs in Axl(-/-) dendritic cells (DCs) in vitro have led to speculation that inhibition of AXL would promote antiviral responses. Notwithstanding, type I IFNs also exert potent immunosuppressive functions. Here we demonstrate that ablation of AXL enhances the susceptibility to infection by influenza A virus and West Nile virus. The increased type I IFN response in Axl(-/-) mice was associated with diminished DC maturation, reduced production of IL-1β, and defective antiviral T cell immunity. Blockade of type I IFN receptor or administration of IL-1β to Axl(-/-) mice restored the antiviral adaptive response and control of infection. Our results demonstrate that AXL is essential for limiting the immunosuppressive effects of type I IFNs and enabling the induction of protective antiviral adaptive immunity.
- Published
- 2016
- Full Text
- View/download PDF
46. TAM receptor signaling in immune homeostasis.
- Author
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Rothlin CV, Carrera-Silva EA, Bosurgi L, and Ghosh S
- Subjects
- Animals, Disease Susceptibility, Humans, Ligands, Receptor Protein-Tyrosine Kinases chemistry, Receptor Protein-Tyrosine Kinases genetics, Homeostasis, Immunity physiology, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction
- Abstract
The TAM receptor tyrosine kinases (RTKs)-TYRO3, AXL, and MERTK-together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease.
- Published
- 2015
- Full Text
- View/download PDF
47. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer.
- Author
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Bosurgi L, Bernink JH, Delgado Cuevas V, Gagliani N, Joannas L, Schmid ET, Booth CJ, Ghosh S, and Rothlin CV
- Subjects
- Animals, Apoptosis genetics, Apoptosis immunology, Azoxymethane, Colitis chemically induced, Colitis genetics, Colon immunology, Colon metabolism, Colon pathology, Colonic Neoplasms chemically induced, Colonic Neoplasms genetics, Cytokines genetics, Cytokines immunology, Dextran Sulfate, Female, Flow Cytometry, Gene Expression immunology, Macrophages immunology, Macrophages metabolism, Male, Mice, Mice, Inbred Strains, Mice, Knockout, Mucous Membrane immunology, Mucous Membrane metabolism, Mucous Membrane pathology, Neutrophils immunology, Neutrophils metabolism, Phagocytosis genetics, Phagocytosis immunology, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Signal Transduction immunology, c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Colitis immunology, Colonic Neoplasms immunology, Proto-Oncogene Proteins immunology, Receptor Protein-Tyrosine Kinases immunology
- Abstract
The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammation-associated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.
- Published
- 2013
- Full Text
- View/download PDF
48. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response.
- Author
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Carrera Silva EA, Chan PY, Joannas L, Errasti AE, Gagliani N, Bosurgi L, Jabbour M, Perry A, Smith-Chakmakova F, Mucida D, Cheroutre H, Burstyn-Cohen T, Leighton JA, Lemke G, Ghosh S, and Rothlin CV
- Subjects
- Animals, Cells, Cultured, Colitis genetics, Colitis immunology, Cytokines immunology, Cytokines metabolism, Dendritic Cells metabolism, Flow Cytometry, Gene Expression immunology, Humans, Immunoblotting, Lymphocyte Activation immunology, Mice, Mice, Knockout, Mice, Transgenic, Protein S genetics, Protein S metabolism, Receptor Protein-Tyrosine Kinases metabolism, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes metabolism, Adaptive Immunity immunology, Dendritic Cells immunology, Protein S immunology, Receptor Protein-Tyrosine Kinases immunology, Signal Transduction immunology, T-Lymphocytes immunology
- Abstract
Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
49. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.
- Author
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Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O'Connor W Jr, Murphy AJ, Valenzuela DM, Yancopoulos GD, Booth CJ, Cho JH, Ouyang W, Abraham C, and Flavell RA
- Subjects
- Animals, Colitis complications, Colitis metabolism, Colitis pathology, Colon metabolism, Colon pathology, Colonic Neoplasms complications, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Disease Models, Animal, Down-Regulation, Epithelial Cells metabolism, Epithelial Cells pathology, Genes, APC, Interleukin-18 metabolism, Interleukins deficiency, Interleukins genetics, Interleukins metabolism, Mice, Mice, Knockout, Receptors, Interleukin deficiency, Receptors, Interleukin genetics, Time Factors, Weight Loss, Interleukin-22, Cell Transformation, Neoplastic, Inflammasomes metabolism, Intestinal Mucosa metabolism, Intestines pathology, Receptors, Interleukin metabolism
- Abstract
Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.
- Published
- 2012
- Full Text
- View/download PDF
50. Transplanted mesoangioblasts require macrophage IL-10 for survival in a mouse model of muscle injury.
- Author
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Bosurgi L, Corna G, Vezzoli M, Touvier T, Cossu G, Manfredi AA, Brunelli S, and Rovere-Querini P
- Subjects
- Animals, Blotting, Western, Cell Differentiation, Cell Separation, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Fluorescent Antibody Technique, Interleukin-10 immunology, Macrophages immunology, Mice, Mice, Inbred C57BL, Muscle Fibers, Skeletal metabolism, Pericytes metabolism, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Stem Cell Transplantation, Stem Cells metabolism, Interleukin-10 metabolism, Macrophages metabolism, Muscle Fibers, Skeletal cytology, Muscle, Skeletal injuries, Pericytes cytology, Stem Cells cytology
- Abstract
The aim of this study was to verify whether macrophages influence the fate of transplanted mesoangioblasts--vessel-associated myogenic precursors--in a model of sterile toxin-induced skeletal muscle injury. We have observed that in the absence of macrophages, transplanted mesoangioblasts do not yield novel fibers. Macrophages retrieved from skeletal muscles at various times after injury display features that resemble those of immunoregulatory macrophages. Indeed, they secrete IL-10 and express CD206 and CD163 membrane receptors and high amounts of arginase I. We have reconstituted the muscle-associated macrophage population by injecting polarized macrophages before mesoangioblast injection: alternatively activated, immunoregulatory macrophages only support mesoangioblast survival and function. This action depends on the secretion of IL-10 in the tissue. Our results reveal an unanticipated role for tissue macrophages in mesoangioblast function. Consequently, the treatment of muscle disorders with mesoangioblasts should take into consideration coexisting inflammatory pathways, whose activation may prove crucial for its success.
- Published
- 2012
- Full Text
- View/download PDF
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