TMEM173 Drives Lethal Coagulation in Sepsis

Cell Host Microbe. 2020 Apr 8;27(4):556-570.e6. doi: 10.1016/j.chom.2020.02.004. Epub 2020 Mar 5.

Abstract

The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes. The TMEM173-dependent increase in cytosolic calcium drives Gasdermin D (GSDMD) cleavage and activation, which triggers the release of F3, the key initiator of blood coagulation. Genetic or pharmacological inhibition of the TMEM173-GSDMD-F3 pathway blocks systemic coagulation and improves animal survival in three models of sepsis (cecal ligation and puncture or bacteremia with Escherichia coli or Streptococcus pneumoniae infection). The upregulation of the TMEM173 pathway correlates with the severity of disseminated intravascular coagulation and mortality in patients with sepsis. Thus, TMEM173 is a key regulator of blood clotting during lethal bacterial infections.

Keywords: ER stress; GSDMD; STING; TMEM173; calcium; coagulation; inflammasome; pyroptosis; sepsis; tissue factor.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Infections
  • Blood Coagulation*
  • Calcium / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Membrane Proteins / metabolism*
  • Mice
  • Monocytes
  • Phosphate-Binding Proteins / metabolism
  • Pyroptosis
  • Sepsis* / metabolism
  • Sepsis* / mortality
  • Signal Transduction
  • THP-1 Cells

Substances

  • GSDMD protein, human
  • Gsdmd protein, mouse
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphate-Binding Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Calcium