Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling
Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling
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DOI：
10.1182/blood-2006-06-015461
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
de Haas, Carla J. C.
中科院分区：
文献类型：
--
作者：
Bestebroer, Jovanka;Poppelier, Miriam J. J. G.;de Haas, Carla J. C.
金黄色葡萄球菌分泌几种干扰宿主细胞功能的毒力因子。葡萄球菌超抗原样蛋白（SSL）是一个由11种外毒素组成的家族，与超抗原具有结构同源性，但功能通常未知。最近，我们描述了金黄色葡萄球菌的趋化抑制蛋白（CHIPS 31 -121），一种有效的C5 a诱导的反应的抑制剂，在结构上与SSL 5的C-末端结构域同源。在这里，我们确定P-选择素糖蛋白配体-1（PSGL-1），参与中性粒细胞沿着内皮的初始滚动，作为SSL 5的靶点。SSL 5与稳定表达PSGL-1的中国仓鼠卵巢细胞（CHO-PSGL-1）特异性结合，这依赖于硫酸化和唾液酸化。此外，SSL 5与固定在生物传感器芯片上的PSGL-1/Ig融合蛋白结合。SSL 5影响可溶性P-选择素/Fc嵌合体（PSGL-1的主要配体）与CHO-PSGL-1细胞的结合，并在静态条件下抑制中性粒细胞与固定化P-选择素的粘附。在流动条件下，SSL 5强烈降低中性粒细胞在固定的P-选择素/Fc和活化的人内皮细胞上的滚动。总之，SSL 5干扰PSGL-1和P-选择素之间的相互作用，表明金黄色葡萄球菌使用SSL 5来防止中性粒细胞向感染部位外渗。这使得SSL 5成为开发新的抗炎化合物的潜在领导者，用于以白细胞过度募集为特征的疾病。
Staphylococcus aureus secretes several virulence factors interfering with host-cell functions. Staphylococcal superantigen-like (SSL) proteins are a family of 11 exotoxins with structural homology to superantigens but with generally unknown functions. Recently, we described that chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS31-121), a potent inhibitor of C5a-induced responses, is structurally homologous to the C-terminal domain of SSL5. Here, we identify P-selectin glycoprotein ligand-1 (PSGL-1), involved in the initial rolling of neutrophils along the endothelium, as a target for SSL5. SSL5 specifically bound to Chinese hamster ovary cells stably expressing PSGL-1 (CHO-PSGL-1), which was dependent of sulfation and sialylation. Furthermore, SSL5 bound to PSGL-1/lg fusion protein immobilized on a biosensor chip. SSL5 affected binding of soluble P-selectin/Fc chimera, the principle ligand of PSGL-1, to CHO-PSGL-1 cells and inhibited adhesion of neutrophils to immobilized P-selectin under static conditions. Under flow conditions SSL5 strongly decreased neutrophil rolling on immobilized P-selectin/Fc and activated human endothelial cells. In conclusion, SSL5 interferes with the interaction between PSGL-1 and P-selectin, suggesting that S aureus uses SSL5 to prevent neutrophil extravasation toward the site of infection. This makes SSL5 a potential lead for the development of new anti-inflammatory compounds for disorders characterized by excessive recruitment of leukocytes.