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المؤلفون: Olivier Benveniste, Varun K. Sharma, Maxime Lecerf, Anupama Karnam, Emmanuel Stephen-Victor, Bharat Bhatt, Fabian Käsermann, Veerupaxagouda Patil, Kithiganahalli Narayanaswamy Balaji, Jagadeesh Bayry, Naresh Rambabu, Srini V. Kaveri, Mrinmoy Das, Laurent Gilardin, Patrick Bruneval
المساهمون: Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Microbiology and Cell Biology [Bangalore, India], Université Paris Descartes - Paris 5 (UPD5), CSL Behring, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de recherche en myologie, Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immuno-pathologie et immuno-intervention thérapeutique = Immunopathology and Therapeutic Immuno-intervention [CRC], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Indian Institute of Science [Bangalore] (IISc Bangalore), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), CLS Behring AG, Bern, Service d'Anatomie et de Cytologie Pathologique (SACP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Jagadeesh, Bayry, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Thérapie des maladies du muscle strié, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)
المصدر: Cell Death and Disease
Cell Death and Disease, Nature Publishing Group, 2020, ⟨10.1038/s41419-020-2249-y⟩
Cell Death and Disease, 2020, 11 (1), pp.50. ⟨10.1038/s41419-020-2249-y⟩
Cell Death and Disease, Nature Publishing Group, 2020, 11 (1), pp.50. ⟨10.1038/s41419-020-2249-y⟩
Cell Death and Disease, Vol 11, Iss 1, Pp 1-14 (2020)
Cell Death & Diseaseمصطلحات موضوعية: Lipopolysaccharides, Cancer Research, medicine.medical_treatment, Anti-Inflammatory Agents, Autoimmunity, medicine.disease_cause, p38 Mitogen-Activated Protein Kinases, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, 0302 clinical medicine, hemic and lymphatic diseases, Phosphorylation, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Microbiology & Cell Biology, 0303 health sciences, biology, lcsh:Cytology, TOR Serine-Threonine Kinases, Immunoglobulins, Intravenous, Endocytosis, Tissue Donors, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Beclin-1, Immunotherapy, Antibody, [SDV.IMM] Life Sciences [q-bio]/Immunology, p38 mitogen-activated protein kinases, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Cell Line, Proinflammatory cytokine, Immunoglobulin Fab Fragments, 03 medical and health sciences, Cellular and Molecular Neuroscience, Immune system, Autophagy, medicine, Humans, lcsh:QH573-671, 030304 developmental biology, Organelles, Innate immune system, business.industry, Macrophages, Adenylate Kinase, Dendritic Cells, Cell Biology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Translational research, Immunity, Innate, Leukocytes, Mononuclear, biology.protein, Phosphatidylinositol 3-Kinase, business, 030215 immunology
الوصف: Autophagy plays an important role in the regulation of autoimmune and autoinflammatory responses of the immune cells. Defective autophagy process is associated with various autoimmune and inflammatory diseases. Moreover, in many of these diseases, the therapeutic use of normal immunoglobulin G or intravenous immunoglobulin (IVIG), a pooled normal IgG preparation, is well documented. Therefore, we explored if IVIG immunotherapy exerts therapeutic benefits via induction of autophagy in the immune cells. Here we show that IVIG induces autophagy in peripheral blood mononuclear cells (PBMCs). Further dissection of this process revealed that IVIG-induced autophagy is restricted to inflammatory cells like monocytes, dendritic cells, and M1 macrophages but not in cells associated with Th2 immune response like M2 macrophages. IVIG induces autophagy by activating AMP-dependent protein kinase, beclin-1, class III phosphoinositide 3-kinase and p38 mitogen-activated protein kinase and by inhibiting mammalian target of rapamycin. Mechanistically, IVIG-induced autophagy is F(ab′)2-dependent but sialylation independent, and requires endocytosis of IgG by innate cells. Inhibition of autophagy compromised the ability of IVIG to suppress the inflammatory cytokines in innate immune cells. Moreover, IVIG therapy in inflammatory myopathies such as dermatomyositis, antisynthetase syndrome and immune-mediated necrotizing myopathy induced autophagy in PBMCs and reduced inflammatory cytokines in the circulation, thus validating the translational importance of these results. Our data provide insight on how circulating normal immunoglobulins maintain immune homeostasis and explain in part the mechanism by which IVIG therapy benefits patients with autoimmune and inflammatory diseases.
وصف الملف: application/pdf; application/msword; image/tiff
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المؤلفون: Thierry Fontaine, Anne Beauvais, Vishukumar Aimanianda, Jean-Paul Latgé, Sahana Holla, Anupama Karnam, Pushpa Hegde, Kithiganahalli Narayanaswamy Balaji, Emmanuel Stephen-Victor, Jagadeesh Bayry, Praveen Prakhar, Srini V. Kaveri, Mrinmoy Das
المساهمون: Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Aspergillus, Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), Indian Institute of Science [Bangalore] (IISc Bangalore), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Institut Pasteur [Paris] (IP), Bayry, Jagadeesh, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
المصدر: Journal of Infectious Diseases
Journal of Infectious Diseases, Oxford University Press (OUP), 2017, 216 (10), pp.1281-1294. ⟨10.1093/infdis/jix469⟩
Journal of Infectious Diseases, 2017, 216 (10), pp.1281-1294. ⟨10.1093/infdis/jix469⟩مصطلحات موضوعية: 0301 basic medicine, Regulatory T cell, Gene Expression, chemical and pharmacologic phenomena, Lymphocyte Activation, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, B7-H1 Antigen, Flow cytometry, Aspergillus fumigatus, 03 medical and health sciences, Interferon-gamma, Mice, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Animals, Humans, IL-2 receptor, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Glucans, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Microbiology & Cell Biology, medicine.diagnostic_test, biology, Chemistry, FOXP3, Dendritic cell, Dendritic Cells, T-Lymphocytes, Helper-Inducer, biology.organism_classification, 3. Good health, Cell biology, TLR2, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Immunology, Cytokines, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Biomarkers, 030215 immunology
الوصف: Background. Human dendritic cell (DC) response to alpha-(1,3)-glucan polysaccharide of Aspergillus fumigatus and ensuing CD4(+) T-cell polarization are poorly characterized. Methods. alpha-(1,3)-Glucan was isolated from A. fumigatus conidia and mycelia cell wall. For the analysis of polarization, DCs and autologous naive CD4(+) T cells were cocultured. Phenotype of immune cells was analyzed by flow cytometry, and cytokines by enzyme-linked immunosorbent assay (ELISA). Blocking antibodies were used to dissect the role of Toll-like receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) in regulating alpha-(1,3)-glucan-mediated DC activation and T-cell responses. DCs from TLR2-deficient mice were additionally used to consolidate the findings. Results. alpha-(1,3)-Glucan induced the maturation of DCs and was dependent in part on TLR2. ``alpha-(1,3)-Glucan-educated'' DCs stimulated the activation of naive T cells and polarized a subset of these cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Mechanistically, Treg stimulation by alpha-(1,3)-glucan was dependent on the PD-L1 pathway that negatively regulated interferon-gamma (IFN-gamma) secretion. Short alpha-(1,3)-oligosaccharides lacked the capacity to induce maturation of DCs but significantly blocked alpha-(1,3)-glucan-induced Treg polarization. Conclusions. PD-L1 dictates the balance between Treg and IFN-gamma responses induced by alpha-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1-PD-L1 to enhance protective immune responses to A. fumigatus infections.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::95d506ebbcef7ef0a2c8548dc87aaebd
https://igi.indrastra.com/items/show/190724 -
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المصدر: Molecular immunology. 68(2 Pt)
مصطلحات موضوعية: beta-Glucans, Immunology, Interleukin-1beta, Primary Cell Culture, Proinflammatory cytokine, Cell Line, Mice, Candida albicans, Animals, Arachidonate 15-Lipoxygenase, Syk Kinase, Hedgehog Proteins, Lectins, C-Type, Molecular Biology, Hedgehog, PI3K/AKT/mTOR pathway, Microbiology & Cell Biology, Arachidonate 5-Lipoxygenase, biology, Tumor Necrosis Factor-alpha, Aspergillus fumigatus, TOR Serine-Threonine Kinases, Pattern recognition receptor, Intracellular Signaling Peptides and Proteins, Protein-Tyrosine Kinases, Interleukin-12, Cell biology, Eicosanoid, Gene Expression Regulation, Cyclooxygenase 2, Arachidonate 5-lipoxygenase, Host-Pathogen Interactions, biology.protein, Macrophages, Peritoneal, Signal transduction, Eicosanoid Production, Aspergillus flavus, Signal Transduction
الوصف: Immune responses during fungal infections are predominately mediated by 5/15-lipoxygenases (LO)-or cyclooxygenase (COX)-2-catalysed bioactive eicosanoid metabolites like leukotrienes, lipoxins and prostaglandins. Although few host mediators of fungi-triggered eicosanoid production have been established, the molecular mechanism of expression and regulation of 5-LO, 15-LO and COX-2 are not well-defined. Here, we demonstrate that, macrophages infected with representative fungi Candida albicans, Aspergillus flavus or Aspergillus fumigatus or those treated with Curdlan, a selective agonist of pattern recognition receptor for fungi Dectin-1, displays increased expression of 5-LO, 15-LO and COX-2. Interestingly, Dectin-1-responsive Syk pathway activates mTOR-sonic hedgehog (SHH) signaling cascade to stimulate the expression of these lipid metabolizing enzymes. Loss-of-function analysis of the identified intermediaries indicates that while Syk-mTOR-SHH pathway-induced 5-LO and 15-LO suppressed the Dectin-l-responsive pro-inflammatory signature cytokines like TNE-alpha, IL-1 beta and IL-12, Syk-mTOR-SHH-induced COX-2 positively regulated these cytokines. Dectin-1-stimulated IL-6, however, is dependent on 5-LO, 15-LO and COX-2 activity. Together, the current study establishes Dectin-1-arbitrated host mediators that direct the differential regulation of immune responses during fungal infections and thus are potential candidates of therapeutic intervention. (C) 2015 Elsevier Ltd. All rights reserved.
وصف الملف: application/pdf
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المؤلفون: Caroline Galeotti, Anupama Karnam, Jagadeesh Bayry, Emmanuel Stephen-Victor, Srini V. Kaveri, Mrinmoy Das
المساهمون: Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d’Hématologie et Rhumatologie Pédiatrique [AP-HP Hôpital Bicêtre], Centre de Référence Maladies constitutionnelles du Globule rouge [AP-HP Hôpital Bicêtre]-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), This study was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie, Université Paris Descartes, and CSL Behring, Switzerland. C.G. is a recipient of fellowship from La Fondation pour la Recherche Médicale (FDM20150633674), France, and E.S.-V. and A.K. are recipients of fellowships from the Indo-French Center for Promotion of Advanced Research., Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
المصدر: Journal of Allergy and Clinical Immunology
Journal of Allergy and Clinical Immunology, Elsevier, 2017, 139 (4), pp.1403-1404.e1. ⟨10.1016/j.jaci.2016.09.062⟩
Journal of Allergy and Clinical Immunology, Elsevier, 2017, ⟨10.1016/j.jaci.2016.09.062⟩
Journal of Allergy and Clinical Immunology, 2017, 139 (4), pp.1403-1404.e1. ⟨10.1016/j.jaci.2016.09.062⟩
Journal of Allergy and Clinical Immunology, Elsevier, 2017, 〈10.1016/j.jaci.2016.09.062〉مصطلحات موضوعية: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, education, Immunology, Receptors, Cell Surface, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mannans, 03 medical and health sciences, 0302 clinical medicine, Allergoids, otorhinolaryngologic diseases, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Humans, Immunology and Allergy, Lectins, C-Type, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Receptor, Mannan, Mannan-binding lectin, Vaccines, biology, Plant Extracts, Cell adhesion molecule, food and beverages, Lectin, hemic and immune systems, Dendritic Cells, Immunotherapy, Allergens, Basophils, Cell biology, carbohydrates (lipids), DC-SIGN, Mannose-Binding Lectins, 030104 developmental biology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cell Adhesion Molecules, Mannose Receptor, Mannose receptor, 030215 immunology
الوصف: Comment inReply. [J Allergy Clin Immunol. 2017]Comment onNovel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1. [J Allergy Clin Immunol. 2016]; International audience; Sirvent et al1 recently showed that novel vaccines targeting dendritic cells (DCs) by coupling glutaraldehyde-polymerized grass pollen allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1. Mechanistically, they found that nonoxidized mannan-coupled glutaraldehyde-polymerized grass pollen allergoids are captured and internalized by 2 lectin receptors on DCs: mannose receptor (CD206) and DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN or CD209). These data thus indicated that DCs could be targeted by C-type lectin receptors for efficient allergen immunotherapy.
وصف الملف: application/pdf
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المؤلفون: Anupama Karnam, Kithiganahalli Narayanaswamy Balaji, Tanushree Mukherjee, Kasturi Mahadik, Pankti Parikh, Praveen Prakhar, S. G. Ramachandra, Vikas Pratap Singh, Amit Singh, R. S. Rajmani, Sahana Holla
المصدر: PLoS Pathogens
PLoS Pathogens, Vol 12, Iss 8, p e1005814 (2016)مصطلحات موضوعية: 0301 basic medicine, Jumonji Domain-Containing Histone Demethylases, Small interfering RNA, Fluorescent Antibody Technique, Artificial Gene Amplification and Extension, Biochemistry, Polymerase Chain Reaction, White Blood Cells, Mice, Cell Signaling, Animal Cells, Gene expression, Medicine and Health Sciences, Small interfering RNAs, lcsh:QH301-705.5, Microbiology & Cell Biology, Notch Signaling, Regulation of gene expression, Granuloma, biology, RNA-Binding Proteins, Lipids, Immunohistochemistry, Cell biology, Nucleic acids, Granulomas, Cellular Types, Intracellular, Research Article, Signal Transduction, lcsh:Immunologic diseases. Allergy, Chromatin Immunoprecipitation, Immunoprecipitation, Immune Cells, Immunoblotting, Immunology, Notch signaling pathway, Molecular Probe Techniques, Nerve Tissue Proteins, Research and Analysis Methods, Real-Time Polymerase Chain Reaction, Transfection, Microbiology, 03 medical and health sciences, Virology, Genetics, Animals, Tuberculosis, Non-coding RNA, Molecular Biology Techniques, Molecular Biology, Mycobacterium Infections, Blood Cells, Macrophages, Biology and Life Sciences, Cell Biology, Reverse Transcriptase-Polymerase Chain Reaction, Gene Expression Regulation, Bacterial, Mycobacterium tuberculosis, Molecular biology, Gene regulation, Disease Models, Animal, 030104 developmental biology, lcsh:Biology (General), biology.protein, RNA, Demethylase, Parasitology, lcsh:RC581-607, Chromatin immunoprecipitation
الوصف: Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M. tuberculosis H37Rv-, MDR-JAL2287-, H37Ra- and M. bovis BCG-induced genes essential for FM generation in a TLR2-dependent manner. Further, NOTCH1-responsive RNA-binding protein MUSASHI (MSI), targets a transcriptional repressor of JMJD3, Msx2-interacting nuclear target protein, to positively regulate infection-induced JMJD3 expression, FM generation and M2 phenotype. Investigations in in vivo murine models further substantiated these observations. Together, our study has attributed novel roles for JMJD3 and its regulators during mycobacterial infection that assist FM generation and fine-tune associated host immunity.
Author Summary Foamy macrophages (FMs) not only provide a suitable survival niche for the mycobacteria in the granuloma but also are reservoirs for several inflammatory mediators that regulate mycobacterial pathogenesis. Hence, understanding the mechanisms that regulate infection-induced FM generation assumes importance. In this investigation, we present empirical evidence to support the role of host epigenetic mechanisms in generating FMs and thus facilitating mycobacterial persistence in vivo. We show that the signaling pathways that mediate mycobacteria-induced expression of JMJD3, a demethylase of the facultative repression mark, regulate the genes assisting in FM generation. Importantly, the identified pathway could largely contribute to the evasive responses during mycobacterial infection and suppression of such pathways during infection could confer stronger immunity. Together, these regulators could be potential candidates for host-directed therapies against mycobacterial infection.وصف الملف: application/pdf
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