The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b
The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b
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DOI：
10.1172/jci40380
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Zhang, Li
中科院分区：
文献类型：
--
作者：
Cao, Chunzhang;Gao, Yamei;Zhang, Li
活化蛋白C（APC）是FDA批准的唯一一种治疗脓毒症的生物活性药物，具有抗凝、抗凝血和屏障保护活性。然而，其潜在的功能的机制没有得到很好的定义。在这里，我们报告APC对巨噬细胞的粘附活性依赖于整合素CD 11b/CD 18，而不是内皮蛋白C受体（EPCR）。我们发现，CD 11b/CD 18结合APC内专门的膜微区/脂筏和促进APC切割和蛋白酶激活受体1（PAR 1）的激活，导致鞘氨醇-1-磷酸（SIP）的产生增强和抑制激活的巨噬细胞的促炎反应。APC的γ-羧基谷氨酸结构域是其抗凝活性和EPCR依赖性屏障保护的关键区域，缺失该结构域对其抗凝血功能没有影响。CD 11b、PAR 1或鞘氨醇激酶-1的基因失活，而不是EPCR，消除了APC在体外抑制巨噬细胞炎症反应的能力。使用LPS诱导的致死性内毒素血症小鼠模型，我们发现APC给药降低了野生型小鼠的死亡率，但对CD 11b缺陷型小鼠没有影响。这些数据建立了我们认为是一种新的机制，APC的抗凝血活性在内毒素血症的设置，并提供了明确的证据，APC的抗凝血功能是从它的屏障保护功能和抗凝活性不同。
Activated protein C (APC), the only FDA-approved biotherapeutic drug for sepsis, possesses anticoagulant, antiinflammatory, and barrier-protective activities. However, the mechanisms underlying its antiinflammatory functions are not well defined. Here, we report that the antiinflammatory activity of APC on macrophages is dependent on integrin CD11b/CD18, but not on endothelial protein C receptor (EPCR). We showed that CD11b/CD18 bound APC within specialized membrane microdomains/lipid rafts and facilitated APC cleavage and activation of protease-activated receptor-1 (PAR1), leading to enhanced production of sphingosine-l-phosphate (SIP) and suppression of the proinflammatory response of activated macrophages. Deletion of the gamma-carboxyglutamic acid domain of APC, a region critical for its anticoagulant activity and EPCR-dependent barrier protection, had no effect on its antiinflammatory function. Genetic inactivation of CD11b, PAR1, or sphingosine kinase-1, but not EPCR, abolished the ability of APC to suppress the macrophage inflammatory response in vitro. Using an LPS-induced mouse model of lethal endotoxemia, we showed that APC administration reduced the mortality of wild-type mice, but not CD11b-deficient mice. These data establish what we believe to be a novel mechanism underlying the antiinflammatory activity of APC in the setting of endotoxemia and provide clear evidence that the antiinflammatory function of APC is distinct from its barrier-protective function and anticoagulant activities.