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

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

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 anticoagu...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2021-03, Vol.54 (3), p.454-467.e6
Main Authors: Tang, Yiting, Wang, Xiangyu, Li, Zhaozheng, He, Zhihui, Yang, Xinyu, Cheng, Xiaoye, Peng, Yue, Xue, Qianqian, Bai, Yang, Zhang, Rui, Zhao, Kai, Liang, Fang, Xiao, Xianzhong, Andersson, Ulf, Wang, Haichao, Billiar, Timothy R., Lu, Ben
Format: Article
Language:eng
Subjects:
Anticoagulants
Caspase-11
Cell activation
Clinical medicine
Coagulation
Cytokines
Heparin
HMGB1 protein
Immune response
Immunomodulation
Innate immunity
Lethality
Lipopolysaccharides
Macrophages
Medicin och hälsovetenskap
non-canonical inflammasome
Plasma
Polysaccharides
Sepsis
Tumor necrosis factor-TNF
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Summary: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. [Display omitted] •Heparin prevents caspase-11-dependent immune responses and lethality in sepsis•Non-anticoagulant heparin prevents caspase-11-dependent coagulation and lethality•Heparin inhibits caspase-11 activation by blocking cytosolic delivery of LPS•Glycocalyx degradation, prevented by heparin, promotes cytosolic delivery of LPS Caspase-11, a cytosolic receptor of LPS, triggers lethal immune responses in sepsis. Tang et al. reveal that heparin prevents cytosolic delivery of LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx degradation and the HMGB1-LPS interaction.
ISSN:1074-7613
1097-4180
1097-4180