The inflammasome pyrin contributes to pertussis toxin-induced IL-1β synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis

PLoS Pathog. 2014 May 29;10(5):e1004150. doi: 10.1371/journal.ppat.1004150. eCollection 2014 May.

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.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Inflammasomes / immunology*
  • Interleukin-1beta / biosynthesis*
  • Interleukin-1beta / immunology
  • Interleukin-6 / metabolism
  • Mice
  • Multiple Sclerosis / metabolism
  • Myeloid Cells
  • Neutrophils / drug effects*
  • Pertussis Toxin / pharmacology*
  • T-Lymphocytes / immunology

Substances

  • Inflammasomes
  • Interleukin-1beta
  • Interleukin-6
  • Pertussis Toxin

Grant support

This work was supported by grants from the Multiple Sclerosis Society of Canada and the Natural Sciences and Engineering Research Council of Canada. LV and SL received Chercheur-Boursier Sénior awards from the Fonds de Recherche du Québec en Santé (FRQS). NA received a postdoctoral fellowship from the FRQS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.