Elphick Gwendolyn F, Sarangi Pranita P, Hyun Young-Min, Hollenbaugh Joseph A, Ayala Alfred, Biffl Walter L, Chung Hung-Li, Rezaie Alireza R, McGrath James L, Topham David J, Reichner Jonathan S, Kim Minsoo
Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, RI, USA.
Blood. 2009 Apr 23;113(17):4078-85. doi: 10.1182/blood-2008-09-180968. Epub 2009 Feb 24.
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.
整合素介导的细胞迁移是许多生物学和病理学过程的核心。在炎症过程中，组织损伤是由活化白细胞的过度浸润和滞留引起的。重组人活化蛋白C（rhAPC）已被证明可保护严重脓毒症患者，但其保护作用的潜在机制仍不清楚。在此，我们表明rhAPC在体外和体内均直接结合β(1)和β(3)整合素并抑制中性粒细胞迁移。我们发现人APC具有精氨酸-甘氨酸-天冬氨酸（RGD）序列，该序列对于抑制作用至关重要。该序列的突变消除了整合素结合和中性粒细胞迁移抑制。此外，用RGD肽治疗脓毒症小鼠概括了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，这种相互作用减少了中性粒细胞向组织中的募集，为rhAPC可能预防脓毒症提供了一种潜在机制。
