Recombinant human activated protein C inhibits integrin-mediated neutrophil migration.
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.
Elphick
Gwendolyn F
GF
Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, RI, USA.
Sarangi
Pranita P
PP
Hyun
Young-Min
YM
Hollenbaugh
Joseph A
JA
Ayala
Alfred
A
Biffl
Walter L
WL
Chung
Hung-Li
HL
Rezaie
Alireza R
AR
McGrath
James L
JL
Topham
David J
DJ
Reichner
Jonathan S
JS
Kim
Minsoo
M
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D016023:Integrins; D011486:Protein C; D011994:Recombinant Proteins