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 (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; P < .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.

中文翻译：

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XIa 因子对 Prochemerin 的裂解与凝血和炎症有关


Chemerin 是一种趋化剂和脂肪因子，以无活性的原凯莫林 (chem163S) 形式在血液中循环。 Chem163S 由一系列 C 末端蛋白水解裂解激活，产生具有不同活性水平的多种凯莫瑞形式。我们筛选了一组参与凝血、纤溶和炎症级联反应的蛋白酶，以鉴定那些在血浆中处理凯莫瑞原的酶。因子 XIa (FXIa) 裂解 chem163S，生成新的凯莫瑞形式，chem162R（作为中间产物）和 chem158K（作为最终产物）。在 Lys158 处裂解或凯莫瑞生物活性的调节不需要在 Arg162 处进行加工。高岭土对人贫血小板血浆的接触相激活导致 chem163S 裂解，这种裂解在 FXI 耗尽的血浆中检测不到，但在富血小板血浆 (PRP) 中显着增强。 PRP 中多磷酸盐的接触相激活导致 chem163S 裂解 75%。这种裂解被水蛭素部分抑制，水蛭素可阻止 FXI 的凝血酶激活。血浆激活后，最有效形式的凯莫瑞 chem157S 以及无活性的 chem155A 的水平增加。与匹配的对照组相比，FXI 缺陷患者的 chem163S 血浆水平显着升高（91 ± 10 ng/mL vs 58 ± 3 ng/mL，n = 8；P < .01），并且与血浆 FXI 水平呈负相关。因此，接触相激活时生成的 FXIa 会裂解 chem163S 生成 chem158K，后者可以进一步加工成最活跃的凯莫瑞形式，从而提供凝血和炎症之间的分子联系。