Prochemerin cleavage by factor XIa links coagulation and inflammation
Prochemerin cleavage by factor XIa links coagulation and inflammation
复制标题
DOI：
10.1182/blood-2017-07-792580
复制
发表时间：
2018-01-18
期刊：
影响因子：
20.3
通讯作者：
Morser, John
中科院分区：
文献类型：
--
作者：
Ge, Xiaomei;Yamaguchi, Yasuto;Morser, John
Chemerin是一种化学引诱物和脂肪因子，作为无活性的前chemerin（chem 163 S）在血液中循环。Chem 163 S通过一系列C-末端蛋白水解裂解激活，产生具有不同活性水平的多种chemerin形式。我们筛选了凝血、纤溶和炎症级联反应中的一组蛋白酶，以鉴定那些在血浆中加工prochemerin的蛋白酶。因子XIa（FXIa）裂解chem 163 S，产生一种新的趋化蛋白形式chem 162 R作为中间产物，chem 158 K作为最终产物。在Arg 162处的加工不需要在Lys 158处切割或调节chemerin生物活性。高岭土对人贫血小板血浆的接触相活化导致chem 163 S裂解，这在FXI耗尽血浆中检测不到，在富血小板血浆（PRP）中显著增强。PRP中多磷酸盐的接触相活化导致chem 163 S的75%裂解。这种切割被水蛭素部分抑制，水蛭素阻断FXI的凝血酶活化。在血浆活化后，chemerin的最有效形式chem 157 S以及无活性chem 155 A的水平增加。与匹配的对照组相比，FXI缺陷患者的chem 163 S血浆水平显著升高（916 10 ng/mL vs 5863 ng/mL，n 58; P
Chemerin is a chemoattractant and adipokine that circulates in blood as inactive pro-chemerin (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 (916 10 ng/mL vs 5863 ng/mL, n58; P