Distinct Commensals Induce Interleukin-1β via NLRP3 Inflammasome in Inflammatory Monocytes to Promote Intestinal Inflammation in Response to Injury

Immunity. 2015 Apr 21;42(4):744-55. doi: 10.1016/j.immuni.2015.03.004. Epub 2015 Apr 7.

Abstract

The microbiota stimulates inflammation, but the signaling pathways and the members of the microbiota involved remain poorly understood. We found that the microbiota induces interleukin-1β (IL-1β) release upon intestinal injury and that this is mediated via the NLRP3 inflammasome. Enterobacteriaceae and in particular the pathobiont Proteus mirabilis, induced robust IL-1β release that was comparable to that induced by the pathogen Salmonella. Upon epithelial injury, production of IL-1β in the intestine was largely mediated by intestinal Ly6C(high) monocytes, required chemokine receptor CCR2 and was abolished by deletion of IL-1β in CCR2(+) blood monocytes. Furthermore, colonization with P. mirabilis promoted intestinal inflammation upon intestinal injury via the production of hemolysin, which required NLRP3 and IL-1 receptor signaling in vivo. Thus, upon intestinal injury, selective members of the microbiota stimulate newly recruited monocytes to induce NLRP3-dependent IL-1β release, which promotes inflammation in the intestine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / immunology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Gene Expression Regulation
  • Hemolysin Proteins / genetics
  • Hemolysin Proteins / immunology
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / microbiology
  • Inflammation / pathology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Intestines / immunology
  • Intestines / injuries
  • Intestines / microbiology
  • Macrophages / immunology
  • Macrophages / microbiology
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microbiota / immunology*
  • Monocytes / immunology*
  • Monocytes / microbiology
  • Monocytes / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Proteus Infections / genetics
  • Proteus Infections / immunology
  • Proteus Infections / microbiology
  • Proteus Infections / pathology
  • Proteus mirabilis / immunology
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / immunology
  • Salmonella / immunology
  • Salmonella Infections / genetics
  • Salmonella Infections / immunology
  • Salmonella Infections / microbiology
  • Salmonella Infections / pathology
  • Signal Transduction
  • Symbiosis / immunology*

Substances

  • Antigens, Ly
  • Carrier Proteins
  • Ccr2 protein, mouse
  • Hemolysin Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Ly-6C antigen, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Receptors, CCR2