Prochemerin cleavage by factor XIa links coagulation and inflammation

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 Arg was not required for cleavage at Lys 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 (PRP). Contact phase activation by polyphosphate in PRP resulted in 75% cleavage of chem163S. This cleavage was partially inhibited by hirudin, which blocks thrombin activation of FXI. After 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 with a matched control group (91 ± 10 ng/mL vs 58 ± 3 ng/mL, n = 8; < .01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated on 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.

Dynamic and tissue-specific proteolytic processing of chemerin in obese mice

“…Activity on CMKLR1 transfected cells in both human and mouse serum from obese individuals did not correlate with the observed increased in chemerin levels. Conversion of plasma to serum will change the spectrum of chemerin forms present [ 22 ]. As different chemerin forms have different activities, the data from serum samples is consistent with the hypothesis that as in plasma [ 33 ] serum from individuals with obesity contains different chemerin forms that are present in different proportions than in serum from individuals with normal BMI.…”

“…Chemerin, also known as retinoic acid receptor responder 2 (RARRES2), is secreted as a precursor (prochemerin) with low biological activity that terminates in humans at amino acid serine 163 (hchem163S). Prochemerin is converted into a full agonist by truncation of the last 6 amino acids at its C-terminus by proteases belonging to the coagulation, fibrinolytic, and inflammatory cascades [ 19 – 22 ]. The most active form of chemerin, hchem157S, can be generated either by direct cleavage of prochemerin by neutrophil-derived serine proteases (elastase or cathepsin G) or tissue-kallikrein [ 23 ], or alternatively by sequential cleavages with clotting factor FXIa or plasmin to form hchem158K followed by removal of the C-terminal lysine by carboxypeptidase N (CPN) or carboxypeptidase B2 (CPB2, also termed thrombin-activatable fibrinolysis inhibitor) producing hchem157S [ 20 ].…”

Network Pharmacology-Guided Development of a Novel Integrative Regimen to Prevent Acute Graft-vs.-Host Disease

“…In two different experiments, XBJ dose-dependently inhibited platelet aggregation, confirming its anti-clotting effect in vivo (Figure 3). Blood clotting directly threatens the survival of allo-HSCT patients and induces inflammation that worsens aGVHD (Ge et al, 2018). XBJ may prevent aGVHD partially through inhibiting clotting and clotting induced inflammation.…”

Plasma Proteolytic Cascade Activation during Neonatal Cardiopulmonary Bypass Surgery

“…[12][13][14][15] In addition, coagulation proteases can cross-activate other plasma proteolytic cascades and vice versa. 16,17 Thus, the neonate undergoing CPB is susceptible to widespread and unregulated proteolysis with consumption of plasma protease inhibitors that regulate blood coagulation, fibrinolysis, complement and inflammation. Members of the serpin superfamily of protease inhibitors undergo large and distinct conformational changes when they interact with proteolytic enzymes.…”