title: The inflammasome pyrin contributes to pertussis toxin-induced IL-1β synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis.
abstract: Microbial agents can aggravate inflammatory diseases, such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). An example is pertussis toxin (PTX), a bacterial virulence factor commonly used as an adjuvant to promote EAE, but whose mechanism of action is unclear. We have reported that PTX triggers an IL-6-mediated signaling cascade that increases the number of leukocytes that patrol the vasculature by crawling on its luminal surface. In the present study, we examined this response in mice lacking either TLR4 or inflammasome components and using enzymatically active and inactive forms of PTX. Our results indicate that PTX, through its ADP-ribosyltransferase activity, induces two series of events upstream of IL-6: 1) the activation of TLR4 signaling in myeloid cells, leading to pro-IL-1β synthesis; and 2) the formation of a pyrin-dependent inflammasome that cleaves pro-IL-1β into its active form. In turn, IL-1β stimulates nearby stromal cells to secrete IL-6, which is known to induce vascular changes required for leukocyte adhesion. Without pyrin, PTX does not induce neutrophil adhesion to cerebral capillaries and is less effective at inducing EAE in transgenic mice with encephalitogenic T lymphocytes. This study identifies the first microbial molecule that activates pyrin, a mechanism by which infections may influence MS and a potential therapeutic target for immune disorders.
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, Quebec, Quebec, Canada.
authors.forename: Aline
authors.initials: A
authors.lastname: Dumas
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, Quebec, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Amiable
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, United States of America.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de Rivero Vaccari
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, United States of America.
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Chae
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miami, Florida, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Keane
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, Quebec, Quebec, Canada; Department of Molecular Medicine, Laval University, Quebec, Quebec, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Lacroix
authors.affiliation: Axis of Neuroscience, University Hospital Center of Quebec, Quebec, Quebec, Canada; Department of Molecular Medicine, Laval University, Quebec, Quebec, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Vallières
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism; D022423:Myeloid Cells; D009504:Neutrophils / Q000187:drug effects*; D037342:Pertussis Toxin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D037342:Pertussis Toxin