Dataset Information

TMEM173 Drives Lethal Coagulation in Sepsis.

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.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7316085 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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TMEM173 Drives Lethal Coagulation in Sepsis.

Zhang Hui H Zeng Ling L Xie Min M Liu Jiao J Zhou Borong B Wu Runliu R Cao Lizhi L Kroemer Guido G Wang Haichao H Billiar Timothy R TR Zeh Herbert J HJ Kang Rui R Jiang Jianxin J Yu Yan Y Tang Daolin D

Cell host & microbe 20200305 4

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 calc ...[more]

PMID: 32142632

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Project description:Backgroundsepsis is a life-threatening organ dysfunction caused by an excessive host immunological response to infection. The incidence of sepsis is increasing every year, and sepsis is the primary cause of mortality in intensive care units (ICUs). DIC is a coagulopathy syndrome that causes microvascular and macrovascular thrombosis and increases the risk of bleeding due to consumptive coagulopathy. The pathophysiology of DIC in sepsis is complex, and further research is required to investigate the involved mechanisms and risk factors.Methodthis study is a prognostic analysis of a retrospective cohort. Samples were patients diagnosed with sepsis and admitted to Cipto Mangunkusumo National General Hospital from January 2016 to October 2022. Research subjects were followed until occurrence of DIC during sepsis or recovery from sepsis. The research subjects were selected from medical records using a consecutive total sampling approach. The inclusion criteria were patients aged ≥18 years old and diagnosed with sepsis according to qSOFA criteria with a score of 2. The exclusion criterion was an incomplete medical record. Bivariate and multivariate logistic regression analyses were performed to determine which independent variables contributed to the incidence of DIC and obtain the odds ratios (ORs). p < 0.05 was considered to indicate a statistically significant difference.Resultsa total of 248 patients were included after considering the inclusion and exclusion criteria. Of these, 50 (20.2%) septic patients developed DIC. In the multivariate analysis, albumin ≤2.5 g/dL (OR: 2.363; 95% CI: 1.201-4.649), respiratory infection (OR: 2.414; 95% CI: 1.046-5.571), and antibiotic treatment ≥1 h (OR: 2.181; 95% CI: 1.014-4.689) were associated with DIC development. On the basis of the ROC curve, the area under the curve (AUC) was determined to be 0.705 with 95% CI = (0.631-0.778).Conclusionin our study, the prevalence of DIC in septic patients was 20.2%. Low albumin, respiratory infection, and antibiotic treatment ≥1 h were found to be risk factors for development of DIC in septic patients.

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TMEM173 Drives Lethal Coagulation in Sepsis.

Publications

TMEM173 Drives Lethal Coagulation in Sepsis.

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