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 Blood, 23 April 2009, Vol. 113, No. 17, pp. 4078-4085.
Prepublished online as a Blood First Edition Paper on February 24, 2009; DOI 10.1182/blood-2008-09-180968.

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PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Recombinant human activated protein C inhibits integrin-mediated neutrophil migration

Gwendolyn F. Elphick1,*, Pranita P. Sarangi2,*, Young-Min Hyun2, Joseph A. Hollenbaugh2, Alfred Ayala1, Walter L. Biffl3, Hung-Li Chung4, Alireza R. Rezaie5, James L. McGrath4, David J. Topham2, Jonathan S. Reichner1, and Minsoo Kim2

1 Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence; 2 Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, NY; 3 Department of Surgery, Denver Health Medical Center, CO; 4 Department of Biomedical Engineering, University of Rochester, NY; and 5 Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO

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 β1 and β3 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.


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