Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection

PLoS Biol. 2020 Sep 29;18(9):e3000813. doi: 10.1371/journal.pbio.3000813. eCollection 2020 Sep.

Abstract

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism*
  • Fatty Acids, Volatile / metabolism*
  • Female
  • Gastrointestinal Microbiome / immunology
  • HEK293 Cells
  • Humans
  • Immunity, Innate / physiology
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism*
  • Macrophage Activation / genetics
  • Macrophage Activation / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Salmonella Infections / genetics
  • Salmonella Infections / immunology
  • Salmonella Infections / metabolism
  • Salmonella Infections / prevention & control*
  • Salmonella typhimurium / immunology
  • U937 Cells

Substances

  • CARD Signaling Adaptor Proteins
  • Fatty Acids, Volatile
  • Ffar2 protein, mouse
  • Inflammasomes
  • Pycard protein, mouse
  • Receptors, G-Protein-Coupled

Grant support

This work was supported by AMED-CREST from the Japan Agency for Medical Research and Development, AMED (to YK, grant no.: JP17gm0710010). The S. Typhimurium infection model in this work was partly supported by Cross-ministerial Strategic Innovation Promotion Program (SIP), “Technologies for creating next-generation agriculture, forestry and fisheries” (funding agency: Bio-oriented Technology Research Advancement Institution, NARO) (to HT). Infrastructures for imaging mass spectrometry and metabolomics were supported in part by Ryoshoku-Kenkyukai and JST ERATO Suematsu Gas Biology Project (M.S.) until FY2015. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.