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TMEM173 Drives Lethal Coagulation in Sepsis

Hui Zhang1, Ling Zeng2, Min Xie1

  • 1Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

Cell Host & Microbe
|March 7, 2020
PubMed

Insights

Myeloid TMEM173 regulates blood clotting during bacterial infections via calcium release and Gasdermin D (GSDMD) activation, independent of interferon. This pathway is crucial for sepsis survival and patient mortality.

Area of Science:

  • Immunology
  • Hematology
  • Molecular Biology

Background:

  • TMEM173/STING-dependent innate immunity is vital for inflammatory disorders.
  • The role of myeloid TMEM173 in coagulation during bacterial infections remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which myeloid TMEM173 regulates coagulation in bacterial infections.
  • To investigate the TMEM173-GSDMD-F3 pathway's role in sepsis and its potential as a therapeutic target.

Main Methods:

  • Investigated TMEM173's role in myeloid cells during bacterial infection models.
  • Utilized genetic and pharmacological inhibition of the TMEM173-GSDMD-F3 pathway.
  • Analyzed TMEM173 pathway upregulation in sepsis patients with disseminated intravascular coagulation.

Main Results:

  • Myeloid TMEM173 regulates coagulation independently of type I interferon response.
  • TMEM173 binding to ITPR1 controls calcium release, activating Gasdermin D (GSDMD) and initiating blood coagulation via F3.
  • Inhibition of the TMEM173-GSDMD-F3 pathway improved survival in sepsis models.
  • TMEM173 pathway upregulation correlated with sepsis severity and mortality.

Conclusions:

  • TMEM173 is a critical regulator of blood clotting in lethal bacterial infections.
  • The TMEM173-GSDMD-F3 pathway represents a novel mechanism linking innate immunity and coagulation.
  • Targeting this pathway offers a potential therapeutic strategy for sepsis and associated coagulopathies.
Keywords:
ER stressGSDMDSTINGTMEM173calciumcoagulationinflammasomepyroptosissepsistissue factor

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