Recombinant human activated protein C inhibits integrin-mediated neutrophil migration
Recombinant human activated protein C inhibits integrin-mediated neutrophil migration
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DOI：
10.1182/blood-2008-09-180968
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发表时间：
2009-04-23
期刊：
影响因子：
20.3
通讯作者：
Kim, Minsoo
中科院分区：
文献类型：
--
作者：
Elphick, Gwendolyn F.;Sarangi, Pranita P.;Kim, Minsoo
整合素介导的细胞迁移是许多生物和病理过程的中心。在炎症期间，组织损伤是由活化白细胞的过度浸润和隔离引起的。重组人活化蛋白C （rhAPC）已被证明可以保护严重脓毒症患者，尽管这种保护作用的机制尚不清楚。在这里，我们发现rhAPC直接结合β(1)和β(3)整合素并抑制中性粒细胞迁移，在体外和体内都是如此。我们发现人类APC具有一个Arg-Gly-Asp （RGD）序列，该序列对抑制作用至关重要。该序列的突变取消了整合素结合和中性粒细胞迁移的抑制。此外，用RGD肽治疗脓毒症小鼠再现了rhAPC对生存的有益作用。因此，我们得出结论，白细胞整合素是rhAPC的新型细胞受体，其相互作用减少了中性粒细胞向组织的募集，这为rhAPC预防败血症提供了一种潜在的机制。（血液。2009;113:4078-4085）
Integrin-mediated cell migration is central to many biologic and pathologic processes. During inflammation, tissue injury results from excessive infiltration and sequestration of activated leukocytes. Recombinant human activated protein C (rhAPC) has been shown to protect patients with severe sepsis, although the mechanism underlying this protective effect remains unclear. Here, we show that rhAPC directly binds to beta(1) and beta(3) integrins and inhibits neutrophil migration, both in vitro and in vivo. We found that human APC possesses an Arg-Gly-Asp (RGD) sequence, which is critical for the inhibition. Mutation of this sequence abolished both integrin binding and inhibition of neutrophil migration. In addition, treatment of septic mice with a RGD peptide recapitulated the beneficial effects of rhAPC on survival. Thus, we conclude that leukocyte integrins are novel cellular receptors for rhAPC and the interaction decreases neutrophil recruitment into tissues, providing a potential mechanism by which rhAPC may protect against sepsis. (Blood. 2009; 113: 4078-4085)