CD45 mediated regulation of PMN function during intestinal inflammation

Abstract: It has been well documented that disease activity in inflammatory mucosal diseases including inflammatory bowel disease is linked to the transepithelial migration of neutrophils through the mucosal epithelium and ultimately into the intestinal lumen. Co-incident with massive luminal influx of neutrophils is uncontrolled release of toxic tissue damaging metabolites that contribute to mucosal and/or transmural injury including edema, loss of goblet cells, decreased mucus production, crypt cell hyperplasia, ulceration and crypt abscess formation. The complex signaling mechanisms that regulate neutrophil transepithelial migration and inflammatory function in mucosal tissues have not been fully elucidated even though excessive neutrophil activation is heavily implicated in disease pathology of IBD and other inflammatory disorders. Preliminary data identifies the tyrosine phosphatase CD45 as an important regulator of neutrophil intestinal infiltration and inflammatory function. This proposal will determine effects of neutrophil specific loss of CD45 on intestinal inflammation and repair using novel neutrophil specific CD45 deficient mice. We will also determine how CD45 phosphatase activity regulates neutrophil intracellular signaling pathways and inflammatory effector functions including migration, degranulation, and superoxide release. Finally using specific antibodies and glycan binding proteins we will determine how specific CD45 isoforms and glycoforms can be targeted to regulate neutrophil activation and inflammatory responses. Elucidating beneficial effects of targeting neutrophil CD45 phosphatase activity during colitis will help to develop novel strategies to ameliorate pathological intestinal inflammation.