Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin α3β1-dependent

Integrin-mediated migration of neutrophils to infected tissue sites is vital for pathogen clearance and therefore host survival. Although beta(2) integrins have been shown to mediate neutrophil transendothelial migration during systemic and local inflammation, relatively little information is available regarding neutrophil migration in sepsis beyond the endothelial cell layer. In this study, we report that integrin alpha(3)beta(1) (VLA-3; CD49c/CD29) is dramatically upregulated on neutrophils isolated from both human septic patients and in mouse models of sepsis. Compared with the alpha(3)beta(low)(1) granulocytes, alpha(3)beta(high)(1) cells from septic animals displayed hyperinflammatory phenotypes. Administration of a alpha(3)beta(1) blocking peptide and conditional deletion of alpha(3) in granulocytes significantly reduced the number of extravasating neutrophils and improved survival in septic mice. In addition, expression of alpha(3)beta(1) on neutrophils was associated with Toll-like receptor-induced inflammatory responses and cytokine productions. Thus, our results show that alpha(3)beta(1) is a novel marker of tissue homing and hyperresponsive neutrophil subtypes in sepsis, and blocking of alpha(3)beta(1) may represent a new therapeutic approach in sepsis treatment.