Research ResourceImmunology

A cluster of immunoresolvents links coagulation to innate host defense in human blood

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Sci. Signal.  01 Aug 2017:
Vol. 10, Issue 490, eaan1471
DOI: 10.1126/scisignal.aan1471

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Linking clots to immunity

The threats to the host posed by barrier breach are counteracted by blood coagulation and the formation of blood clots, processes that are accompanied by inflammation and then tissue regeneration and wound healing. Arachidonic acid–derived prostaglandins and leukotrienes play important prothrombotic and inflammatory roles early in the process, which lead to the generation of other lipid mediators known as specialized proresolving mediators (SPMs), which are important for resolution. Norris et al. used metabololipidomics and mass cytometry–based analyses to identify a functional cluster of SPMs generated at the late stages of human blood coagulation. Treatment of whole blood with these particular SPMs stimulated distinct signaling pathways within specific cell types and enhanced the uptake and killing of bacteria by phagocytic cells. Together, these data connect factors generated by blood coagulation to immune responses that protect the host.

Abstract

Blood coagulation is a protective response that prevents excessive bleeding upon blood vessel injury. We investigated the relationship between coagulation and the resolution of inflammation and infection by lipid mediators (LMs) through metabololipidomics-based profiling of human whole blood (WB) during coagulation. We identified temporal clusters of endogenously produced prothrombotic and proinflammatory LMs (eicosanoids), as well as specialized proresolving mediators (SPMs). In addition to eicosanoids, a specific SPM cluster was identified that consisted of resolvin E1 (RvE1), RvD1, RvD5, lipoxin B4, and maresin 1, each of which was present at bioactive concentrations (0.1 to 1 nM). Removal of adenosine from the coagulating blood markedly enhanced the amounts of SPMs produced and further increased the biosynthesis of RvD3, RvD4, and RvD6. The cyclooxygenase inhibitors celecoxib and indomethacin, which block the production of thromboxanes and prostanoids, did not block the production of clot-driven SPMs. Unbiased mass cytometry analysis demonstrated that the SPM cluster produced in human blood targeted leukocytes at the single-cell level, directly activating ERK and CREB signaling in neutrophils and CD14+ monocytes. Treatment of human WB with the components of this SPM cluster enhanced both the phagocytosis and killing of Escherichia coli by leukocytes. Together, these data identify a proresolving LM circuit, including endogenous molecular brakes and accelerators, which promoted host defense. These temporal LM-SPM clusters can provide accessible metabolomic profiles for precision and personalized medicine.

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