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Prochemerin cleavage by Factor XIa links coagulation and inflammation

Xiaomei Ge, Yasuto Yamaguchi, Lei Zhao, Loredana Bury, Paolo Gresele, Caroline Berube, Lawrence L. Leung and John Morser

Key points

  • Inactive prochemerin is activated in plasma by coagulation enzymes to active chemerin forms that are adipokines and chemoattractants.

  • Factor XIa cleaves prochemerin forming a partially active intermediate that is then fully activated by plasma basic carboxypeptidases.

Abstract

Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product. Processing at Arg162 was not required for cleavage at Lys158 or regulation of chemerin bioactivity. Contact phase activation of human platelet-poor plasma by kaolin led to cleavage of chem163S, which was undetectable in FXI-depleted plasma and markedly enhanced in platelet-rich plasma. Contact phase activation by polyphosphate in platelet-rich plasma resulted in 75% cleavage of chem163S. This cleavage was partially blocked by hirudin, which blocked thrombin activation of FXI. Following activation of plasma, levels of the most potent form of chemerin, chem157S, as well as inactive chem155A, increased. Plasma levels of chem163S in FXI-deficient patients were significantly higher compared to a matched control group (91 ± 10 ng/mL vs. 58 ± 3 ng/mL, n = 8; P<0.01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated upon contact phase activation, cleaves chem163S to generate chem158K, which can be further processed to the most active chemerin form, providing a molecular link between coagulation and inflammation.

  • Submitted July 13, 2017.
  • Accepted November 14, 2017.