Adhesion Receptors and Neutrophil Migration in the Vasculature

$313,595P01FY2014HLNIH

University Of Rochester, Rochester NY

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Abstract

Migration of peripheral blood neutrophils to infection sites is vital for pathogen clearance and thus, host survival. Interaction between cell surface integrins with their counterpart ligands, which are expressed on the endothelial surface, results in the localization and adherence of circulating neutrophils to endothelial cells. This is followed by neutrophil activation and directed migration to sites of infection. An important function of integrins is to concentrate neutrophils at the infection site, ensuring that their immune products and activities remain at this site, while minimizing unnecessary injury to uninfected tissues. Aberrant integrin activation can lead to excessive infiltration and sequestration of activated neutrophils causing tissue injury. Insufficient function of integrin can result in recurrent infection and failure to heal wounds. Therefore, studies of the functions of the integrins and the regulation of cell adhesiveness and migration through them are of great importance in enhancing our ability to develop better-targeted and more effective anti-inflammatory therapies. Although it has been well established that integrins undergo functionally significant conformational changes to mediate cell adhesion, there is no mechanistic information that explains how these are dynamically and spatially regulated during neutrophil migration. This project will study the mechanism of integrin Mac-1 activation during neutrophil migration. We hypothesize that expression of cell surface Mac-1 and its activation occur in a temporally and spatially restricted manner during neutrophil migration. In Aim 1, we will develop fluorescence resonance energy transfer (FRET) based assays to visualize Mac-1 activation on living cell. Studies in Aim 2 will visualize dynamic regulation of Mac-1 activation and its distribution on live migrating cells. Aim 3 will investigate different regulations of Mac-1 and LFA-1 activation during neutrophil migration. In Aim 4, we will study Mac-1 activation in vivo by generating knock-in mice, where aM and P2 subunits of Mac-1 are conjugated to CFP and YFP, respectively. The underlying premise of this proposal is that a better understanding of leukocyte integrin regulation may reveal that integrins represent therapeutic targets for safe and effective regulation of the innate immune system.

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