Clots Are Potent Triggers of Inflammatory Cell Gene Expression

  • Campbell R
  • Vieira-de-Abreu A
  • Rowley J
  • et al.
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Abstract

© 2017 American Heart Association, Inc. 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.

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APA

Campbell, R. A., Vieira-de-Abreu, A., Rowley, J. W., Franks, Z. G., Manne, B. K., Rondina, M. T., … Weyrich, A. S. (2017). Clots Are Potent Triggers of Inflammatory Cell Gene Expression. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(10), 1819–1827. https://doi.org/10.1161/atvbaha.117.309794

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