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Recombinant Activated Protein C Regulates Integrin‐Mediated Neutrophil Migration
Author(s) -
Elphick Gwendolyn F.,
Chen LiiFeng,
Morin Nicole A.,
LeBlanc Brian,
Lavigne Liz M.,
Rezaie Alireza R.,
Biffl Walter,
Reichner Jonathan S.,
Kim Minsoo
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.666.5
Subject(s) - integrin , chemotaxis , chemokine , microbiology and biotechnology , sepsis , immunology , cell migration , infiltration (hvac) , biology , inflammation , chemistry , receptor , cell , biochemistry , physics , thermodynamics
Leukocyte migration to infected tissue is necessary to control pathogenic infections. Migration is mediated through integrin/ligand interactions between immune cells and the blood vessel endothelium or tissue matrix. Migration is modulated by a host of factors present in the bloodstream and the tissues during infection, such as cytokines, chemokines, and bacterial debris. Recombinant human activated protein C (rhAPC) has been shown to modestly increase patients survival during severe sepsis, although the mechanism underlying this protective effect remains unclear. During sepsis, tissue injury results, in part, from excessive infiltration and sequestration of neutrophils in part caused by dysregulation of cell surface adhesion molecules such as integrins. We show that rhAPC binds directly to β1 and β3 integrins and inhibits human neutrophil migration. We found that human APC possesses a RGD sequence, critical for intergrin interactions. Mutation of this sequence (RGD to RGE) abolished integrin binding and inhibition of neutrophil migration. Thus, rhAPC decreases neutrophil recruitment into tissues by blocking neutrophil integrins, providing a potential mechanism by which rhAPC may protect from sepsis. These findings point to a novel target through which neutrophil migration is effected.