Regulating neutrophil response during chronic inflammation through SIRPa alterati

Georgia State University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Neutrophil-mediated inflammatory response is a central component of host defense and also plays a major role in tissue damage as observed in many severe pathophysiological conditions. In studies, we found that PMN undergo phenotypic change during active inflammation and such change is associated with SIRP? alteration in PMN. SIRP? is an essential leukocyte signaling receptor that critically regulates PMN function through extracellular binding interactions with CD47 and intracellular signaling via the immunoreceptor tyrosine-based inhibition motifs (ITIMs). Our hypothesis is that critical inflammatory factors produced at post-acute and chronic stages of inflammation induce deletion of SIRP? ITIMs in PMN resulting in enhanced PMN infiltration and intensified inflammation. Our specific aims are 1) to determine how SIRP? ITIM deletion enhances PMN-mediated inflammatory response, 2) to determine the role of IL-17 in SIRP? ITIM cleavage and identify the responsible protease in PMN, and 3) to determine the therapeutic potential of functional SIRP? ITIM peptides in suppressing PMN infiltration during chronic inflammation. The goal of this project is to discover novel mechanisms underlying dynamic regulation of inflammation and identify new molecular therapeutic targets for drug design in order to alleviate PMN-mediated inflammatory response especially under chronic inflammation.