1. Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages
- Author
-
Reid Oldenburg, Caroline Demangel, Jacques Prandi, Catherine Werts, Christophe Guilhot, Véronique Mayau, Nathalie Winter, Catherine Astarie-Dequeker, Ainhoa Arbues, Immunobiologie de l'Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], Infectiologie Animale et Santé Publique - IASP (Nouzilly, France), Institut National de la Recherche Agronomique (INRA), Université Francois Rabelais [Tours], This study was supported by the 'Marie Skłodowska-Curie Actions' of the European Union’s Seventh Framework Programme FP7/2007-2013, REA grant agreement no. 317057, the French National Research Agency (ANR-11-BSV3-001), Institut Pasteur and Institut National de la Santé et de la Recherche Médicale (INSERM)., European Project: 317057,EC:FP7:PEOPLE,FP7-PEOPLE-2012-ITN,HOMIN(2013), Immunobiologie de l'Infection - Immunobiology of Infection, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Régulation des Infections Rétrovirales, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UPS), Biologie et Génétique de la Paroi bactérienne, Génétique mycobactérienne, GUILHOT, Christophe, Host-microbe interactions in health and disease. Interface with the immune system - HOMIN - - EC:FP7:PEOPLE2013-04-01 - 2017-03-31 - 317057 - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Demangel, Caroline
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Nitric Oxide Synthase Type II ,Complement receptor ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Mice ,glycolipide ,Cell Wall ,Immunologie ,mycobactérie ,Immunology and Allergy ,TLR4 ,TRIF ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,Original Research ,Mice, Knockout ,biology ,Chemistry ,Microbiology and Parasitology ,Microbiologie et Parasitologie ,Cell biology ,Nitric oxide synthase ,iNOS ,Mycobacterium leprae ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,phenolic glycolipids ,Signal transduction ,Tyrosine kinase ,réponse inflammatoire ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,macrophages ,mycobacteria ,Immunology ,macrophage ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,03 medical and health sciences ,Downregulation and upregulation ,Leprosy ,CXCL10 ,Animals ,[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity ,Antigens, Bacterial ,Macrophages ,Interferon-beta ,Chemokine CXCL10 ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Adaptor Proteins, Vesicular Transport ,030104 developmental biology ,biology.protein ,Glycolipids ,lcsh:RC581-607 - Abstract
Phenolic glycolipids (PGLs) are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here we show that in addition, PGLs exert anti-bactericidal activity by limiting the production of nitric oxide synthase (iNOS) in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor (CR)3-dependent, and comparably induced by bacterially-displayed and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the Toll-like receptor (TLR)4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-beta (TRIF) protein level. PGL-driven decrease in TRIF operated post-transcriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-beta and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.
- Published
- 2018
- Full Text
- View/download PDF