Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties

Yiting Tang, Xiangyu Wang, Zhaozheng Li, Zhihui He, Xinyu Yang, Xiaoye Cheng, Yue Peng, Qianqian Xue, Yang Bai, Rui Zhang, Kai Zhao, Fang Liang, Xianzhong Xiao, Ulf Andersson, Haichao Wang, Timothy R. Billiar, Ben Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.

Original languageEnglish
Pages (from-to)454-467.e6
JournalImmunity
Volume54
Issue number3
DOIs
StatePublished - 9 Mar 2021
Externally publishedYes

Keywords

  • Caspase-11
  • coagulation
  • heparin
  • non-canonical inflammasome
  • sepsis

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