Exacerbated tissue homing of neutrophils during sepsis and TLR2-induced cytokine production are regulated by integrin α3β1. (CAM5P.230)

Abstract

Abstract Neutrophil migration to sites of infection is vital for pathogen clearance, but massive neutrophil infiltration during systemic inflammation leads to tissue injury and host mortality. While β2 integrins are well known to mediate neutrophil firm adhesion and crawling, the role of β1 integrins in vascular extravasation has been less explored. In this study, we evaluated the surface expression kinetics of β1 and β3 integrin heterodimers on neutrophils during sepsis using mouse models (CLP and endotoxemia) and human samples. We show that only integrin α3β1 becomes significantly upregulated. Moreover, human subjects with sepsis, but not SIRS (systemic inflammation w/o infection) upregulated α3β1. The increased expression of α3β1 on neutrophils correlated with their activation state. Administration of synthetic peptide (LXY2), which binds at the ligand binding site on α3β1, and conditional gene deletion of the integrin in granulocytes significantly reduced the number of extravasated neutrophils and improved mouse survival. Host bacterial clearance remained unaffected. Interestingly, LXY2 binding to α3β1 on neutrophils was associated with a reduction in TLR2-, but not TLR4-induced IL-10 secretion in vitro. Previous studies suggest a role for IL-10 as a regulator of the transition from mild sepsis to irreversible septic shock. Thus, integrin α3β1 upregulation promotes enhanced neutrophil migration and, in turn, could regulate sepsis progression by modulating neutrophil IL-10 release.