The Plasma Kallikrein-Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice.
The Plasma Kallikrein-Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice.
复制标题
血浆激肽释放酶-激肽原途径在小鼠结肠炎的发病机制中至关重要
DOI：
10.3389/fimmu.2018.00021
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Wang B;Yang A;Zhao Z;He C;Liu Y;Colman RW;Dai J;Wu Y
激肽释放酶-激肽系统(KKS)由前激肽释放酶(PKal)和凝血因子XII(FXII)两种丝氨酸蛋白酶和辅助因子--高分子激肽原(HK)组成。当KKS被激活时，HK被切割以释放缓激肽。虽然KKS在患有炎症性肠病(IBD)的人和动物中被激活，但它在IBD发病机制中的作用尚未确定。在目前的研究中，我们利用缺乏KKS相关蛋白的小鼠来确定KKS在IBD发病机制中的作用。在葡聚糖硫酸钠(DSS)或2，4，6-三硝基苯磺酸(TNBS)诱导的两种结肠炎模型中，HK、pKal或缓激肽受体缺陷的小鼠表现出体重减轻、疾病活动指数、结肠长度缩短、组织学评分和结肠细胞因子产生的表型减弱。HK缺陷小鼠结肠固有层中性粒细胞和炎性单核细胞的浸润减少。通过静脉注射HK重建小鼠对DSS诱导的结肠炎的易感性，提高结肠组织中IL-1β水平和血浆缓激肽浓度。与其他缺乏KKS相关蛋白的小鼠的表型相反，缺乏FXII的小鼠的结肠炎症状与野生型小鼠相似。DSS诱导的小鼠结肠炎后，野生型小鼠血浆中缓激肽浓度明显升高。体外分析表明，DSS诱导的pKal激活、HK裂解和缓激肽血浆释放可被pKal阻断或被抑制。与DSS不同，TNBS诱导的结肠炎不会触发HK裂解。总而言之，我们的数据有力地表明，Kal独立于FXII发挥作用，通过促进缓激肽从香港释放而促进实验性结肠炎。
The kallikrein–kinin system (KKS) consists of two serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-molecular-weight kininogen (HK). Upon activation of the KKS, HK is cleaved to release bradykinin. Although the KKS is activated in humans and animals with inflammatory bowel disease (IBD), its role in the pathogenesis of IBD has not been characterized. In the present study, we determined the role of the KKS in the pathogenesis of IBD using mice that lack proteins involved in the KKS. In two colitis models, induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS), mice deficient in HK, pKal, or bradykinin receptors displayed attenuated phenotypes, including body weight loss, disease activity index, colon length shortening, histological scoring, and colonic production of cytokines. Infiltration of neutrophils and inflammatory monocytes in the colonic lamina propria was reduced in HK-deficient mice. Reconstitution of HK-deficient mice through intravenous injection of HK recovered their susceptibility to DSS-induced colitis, increased IL-1β levels in the colon tissue and bradykinin concentrations in plasma. In contrast to the phenotypes of other mice lacking other proteins involved in the KKS, mice lacking FXII had comparable colonic inflammation to that observed in wild-type mice. The concentration of bradykinin was significantly increased in the plasma of wild-type mice after DSS-induced colitis. In vitro analysis revealed that DSS-induced pKal activation, HK cleavage, and bradykinin plasma release were prevented by the absence of pKal or the inhibition of Kal. Unlike DSS, TNBS-induced colitis did not trigger HK cleavage. Collectively, our data strongly suggest that Kal, acting independently of FXII, contributes to experimental colitis by promoting bradykinin release from HK.