Yang Aizhen, Zhou Junsong, Wang Bo, Dai Jihong, Colman Robert W, Song Wenchao, Wu Yi
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
FASEB J. 2017 Dec;31(12):5419-5431. doi: 10.1096/fj.201700018R. Epub 2017 Aug 14.
The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis. In a K/BxN serum transfer-induced arthritis (STIA) model, mice that lacked HK, pKal, or bradykinin receptors displayed protective phenotypes in joint swelling, histologic changes in inflammation, and cytokine production; however, FXII-deficient mice developed normal arthritis. Inhibition of Kal ameliorated arthritis severity and incidence at early stage STIA and reduced the levels of major cytokines in joints. In addition to releasing bradykinin from HK, Kal directly activated monocytes to produce proinflammatory cytokines, up-regulated their C5aR and FcRIII expression, and released C5a. Immune complex increased pKal activity, which led to HK cleavage. The absence of HK is associated with a decrease in joint vasopermeability. Thus, we identify a critical role for Kal in autoantibody-induced arthritis with pleiotropic effects, which suggests that it is a new target for the inhibition of arthritis.-Yang, A., Zhou, J., Wang, B., Dai, J., Colman, R. W., Song, W., Wu, Y. A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.
血浆激肽释放酶 - 激肽系统（KKS）由丝氨酸蛋白酶、前激肽释放酶（pKal）和因子 XII（FXII）以及一种辅因子高分子量激肽原（HK）组成。激活后，活化的 pKal 和 FXII 裂解 HK 以释放缓激肽。该系统的激活在类风湿性关节炎患者中已有报道，并且其致病作用已在动物关节炎模型中得到表征。在本研究中，我们构建了 2 种缺乏 pKal 和 HK 的基因敲除小鼠品系，并确定了 KKS 在自身抗体诱导的关节炎中的作用。在 K/BxN 血清转移诱导的关节炎（STIA）模型中，缺乏 HK、pKal 或缓激肽受体的小鼠在关节肿胀、炎症组织学变化和细胞因子产生方面表现出保护表型；然而，缺乏 FXII 的小鼠发生正常的关节炎。在 STIA 早期抑制激肽释放酶可改善关节炎严重程度和发病率，并降低关节中主要细胞因子的水平。除了从 HK 释放缓激肽外，激肽释放酶还直接激活单核细胞以产生促炎细胞因子，上调其 C5aR 和 FcRIII 表达，并释放 C5a。免疫复合物增加 pKal 活性，导致 HK 裂解。HK 的缺失与关节血管通透性降低有关。因此，我们确定了激肽释放酶在自身抗体诱导的关节炎中具有多效性的关键作用，这表明它是抑制关节炎的新靶点。 - 杨，A.，周，J.，王，B.，戴，J.，科尔曼，R.W.，宋，W.，吴，Y. 血浆激肽释放酶在自身抗体诱导的关节炎发病机制中的关键作用。
