The Salmonella Pathogenicity island-2 Subverts Human NLRP3 and NLRC4 Inflammasome Responses

J Leukoc Biol. 2019 Feb;105(2):401-410. doi: 10.1002/JLB.MA0318-112RR. Epub 2018 Oct 4.

Abstract

Inflammasomes are signaling hubs that activate inflammatory caspases to drive cytokine maturation and cell lysis. Inflammasome activation by Salmonella Typhimurium infection or Salmonella-derived molecules is extensively studied in murine myeloid cells. Salmonella-induced inflammasome signaling in human innate immune cells, is however, poorly characterized. Here, we show that Salmonella mutation to inactivate the Salmonella pathogenicity island-2 type III secretion system (SPI2 T3SS) potentiates S. Typhimurium-induced inflammasome responses from primary human macrophages, resulting in strong IL-1β production and macrophage death. Inactivation of the SPI1 T3SS diminished human macrophage responses to WT and ΔSPI2 Salmonella. Salmonella ΔSPI2 elicited a mixed inflammasome response from human myeloid cells, in which NLR family CARD-domain containing protein 4 (NLRC4) and NLR family PYRIN-domain containing protein 3 (NLRP3) perform somewhat redundant functions in generating IL-1β and inducing pyroptosis. Our data suggest that Salmonella employs the SPI2 T3SS to subvert SPI1-induced NLRP3 and NLRC4 inflammasome responses in human primary macrophages, in a species-specific immune evasion mechanism.

Keywords: NLRC4; NLRP3; Typhimurium; caspase; pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / metabolism*
  • Calcium-Binding Proteins / metabolism*
  • Cell Death
  • Genomic Islands*
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Pyroptosis
  • Salmonella typhimurium / genetics*

Substances

  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRC4 protein, human
  • NLRP3 protein, human
  • PYCARD protein, human