Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
EMBO J. 2012 Aug 29;31(17):3607-19. doi: 10.1038/emboj.2012.212. Epub 2012 Jul 31.
The CXC chemokine receptor 2 (CXCR2) on neutrophils, which recognizes chemokines produced at the site of infection, plays an important role in antimicrobial host defenses such as neutrophil activation and chemotaxis. Staphylococcus aureus is a successful human pathogen secreting a number of proteolytic enzymes, but their influence on the host immune system is not well understood. Here, we identify the cysteine protease Staphopain A as a chemokine receptor blocker. Neutrophils treated with Staphopain A are unresponsive to activation by all unique CXCR2 chemokines due to cleavage of the N-terminal domain, which can be neutralized by specific protease inhibitors. Moreover, Staphopain A inhibits neutrophil migration towards CXCR2 chemokines. By comparing a methicillin-resistant S. aureus (MRSA) strain with an isogenic Staphopain A mutant, we demonstrate that Staphopain A is the only secreted protease with activity towards CXCR2. Although the inability to cleave murine CXCR2 limits in-vivo studies, our data indicate that Staphopain A is an important immunomodulatory protein that blocks neutrophil recruitment by specific cleavage of the N-terminal domain of human CXCR2.
中性粒细胞上的 CXC 趋化因子受体 2（CXCR2）识别感染部位产生的趋化因子，在中性粒细胞激活和趋化等抗菌宿主防御中发挥重要作用。金黄色葡萄球菌是一种成功的人类病原体，分泌多种蛋白水解酶，但它们对宿主免疫系统的影响尚不清楚。在这里，我们确定半胱氨酸蛋白酶 Staphopain A 是一种趋化因子受体阻断剂。由于 N 端结构域的裂解，用 Staphopain A 处理的中性粒细胞对所有独特的 CXCR2 趋化因子的激活无反应，该裂解可以被特异性蛋白酶抑制剂中和。此外，Staphopain A 抑制中性粒细胞向 CXCR2 趋化因子的迁移。通过比较耐甲氧西林金黄色葡萄球菌（MRSA）菌株和同源的 Staphopain A 突变体，我们证明 Staphopain A 是唯一对 CXCR2 具有活性的分泌蛋白酶。尽管无法裂解鼠 CXCR2 限制了体内研究，但我们的数据表明 Staphopain A 是一种重要的免疫调节蛋白，通过特异性裂解人 CXCR2 的 N 端结构域阻断中性粒细胞的募集。
