Theranostics 2021; 11(9):4251-4261. doi:10.7150/thno.50182

Research Paper

Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5n-3 DPA production

Juan Lei1#, Yu Zhou1#, Huakan Zhao1#, Yu Chen1#, Guifang Yan1, Lei Wu1, Yanquan Xu2, Jiangang Zhang2, Xiao Zhang2, Jingchun Wang2, Dingshan Li2, Yongsheng Li1,2✉

1. Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing 400030, China.
2. Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
#These authors contributed equally to this work.

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Citation:
Lei J, Zhou Y, Zhao H, Chen Y, Yan G, Wu L, Xu Y, Zhang J, Zhang X, Wang J, Li D, Li Y. Dabigatran activates inflammation resolution by promoting fibrinogen-like protein 2 shedding and RvD5n-3 DPA production. Theranostics 2021; 11(9):4251-4261. doi:10.7150/thno.50182. Available from https://www.thno.org/v11p4251.htm

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Abstract

Rationale: The interaction between coagulation and inflammation resolution remains elusive. We recently highlighted a link between fibrinogen-like protein 2 (Fgl2) and a specialized pro-resolving mediator (SPM)-n-3 docosapentaenoic acid-derived resolvin D5 (RvD5n-3 DPA) in sepsis. This study aimed to investigate the functions of commonly used anticoagulants warfarin, dabigatran and heparin in regulating inflammation resolution.

Methods: Peripheral blood was collected from clinical sepsis patients and healthy control for the determination of indicated indexes. Mouse sepsis models of zymosan-induced peritonitis and cecal ligation and puncture (CLP) were employed for the measurement of inflammation- and coagulation-related indexes. Western-blotting, ELISA and flow cytometry were applied to assess proteins. UPLC-MS/MS was used to evaluate lipid metabolites.

Results: Here we report that the transmembrane Fgl2 (mFgl2) was positively associated with coagulation, while soluble Fgl2 (sFgl2) level correlated with the enhanced number of peripheral blood mononuclear cells in the sepsis patients. The anticoagulants dabigatran and warfarin attenuated zymosan-induced peritonitis, which was not shared by heparin, while only dabigatran significantly improved sepsis survival in the CLP sepsis mouse model. Although these anticoagulants consistently inhibited pro-inflammatory mediators including prostaglandin E2 and leukotriene B4, only dabigatran increased sFgl2 at both the initiation and resolution phases of inflammation. Mechanistically, dabigatran elicited the shedding of sFgl2 via prothrombin-related metalloproteases, thereby enhanced the subsequent biosynthesis of RvD5n-3 DPA via STAT6-ALOX15 axis. Blocking metalloproteases or ALOX15 significantly impaired dabigatran-enhanced macrophage efferocytosis in vitro, as well as delayed the dabigatran-accelerated inflammation resolution in vivo.

Conclusions: Our findings identify the dual anti-inflammatory and pro-resolving actions of dabigatran, through promoting sFgl2-triggered RvD5n-3 DPA production, which has important implications for promoting tissue homeostasis of sepsis.

Keywords: fibrinogen-like protein 2, coagulation, sepsis, dabigatran, resolvin