Clots are potent triggers of inflammatory cell gene expression: Indications for timely fibrinolysis

Robert A. Campbell, Adriana Vieira-De-Abreu, Jesse W. Rowley, Zechariah G. Franks, Bhanu Kanth Manne, Matthew T. Rondina, Larry W. Kraiss, Jennifer J. Majersik, Guy A. Zimmerman, Andrew S. Weyrich

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Objective - Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. Approach and Results - We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. Conclusions - These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset.

Original languageEnglish
Pages (from-to)1819-1827
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number10
DOIs
StatePublished - 2017

Keywords

  • Fibrin
  • Fibrinogen
  • Inflammation
  • Monocytes
  • Thrombin

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