Cutting Edge: The Heat Shock Protein gp96 Activates Inflammasome-Signaling Platforms in APCs

J Immunol. 2018 Oct 15;201(8):2209-2214. doi: 10.4049/jimmunol.1800505. Epub 2018 Sep 12.

Abstract

Several heat shock proteins (HSPs) prime immune responses, which are, in part, a result of activation of APCs. APCs respond to these immunogenic HSPs by upregulating costimulatory molecules and secreting cytokines, including IL-1β. These HSP-mediated responses are central mediators in pathological conditions ranging from cancer, sterile inflammation associated with trauma, and rheumatoid arthritis. We tested in this study the requirement of inflammasomes in the release of IL-1β by one immunogenic HSP, gp96. Our results show that murine APCs activate NLRP3 inflammasomes in response to gp96 by K+ efflux. This is shown to initiate inflammatory conditions in vivo in the absence of additional known inflammasome activators or infection. These results document a novel mechanism by which proteins of endogenous origin, the HSPs, can modulate an inflammatory response following their release from aberrant cells.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Inflammasomes / metabolism*
  • Inflammation / immunology*
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Phosphate-Binding Proteins
  • Potassium / metabolism
  • Signal Transduction

Substances

  • Apoptosis Regulatory Proteins
  • Gsdmd protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Phosphate-Binding Proteins
  • endoplasmin
  • Caspase 1
  • Potassium