Disrupting cxcr2 macromolecular complex pdz-domain interactions during inflammatory chemotaxis

DISRUPTING CXCR2 MACROMOLECULAR COMPLEX PDZ-DOMAININTERACTIONS DURING INFLAMMATORY CHEMOTAXISbyMARCELLO P. CASTELVETEREAugust 2012Advisor: Dr. Chunying Li Major: Biochemistry and Molecular BiologyDegree: Master of ScienceNeutrophils are the body’s first responders to inflammation being the mostabundant white blood cell type in circulation and they quickly initiate an immuneresponse through chemokine signaling. Inflammatory chemokines signal via theirreceptor CXCR2, which initiates an inflammatory response, recruiting leukocytes tosites of inflammation. Chemokine signaling is important for proper host protection, yet uncontrolled activity is responsible for a variety of pathological conditions: includingrheumatoid arthritis, ischemia-reperfusion injury, arteriosclerosis, multiple sclerosis,psoriasis, inflammatory bowel disease, and allergic reactions.In this report I show a CXCR2 macromolecular signaling complex exists inneutrophils containing NHERF1 and PLCβ2. I also demonstrate a novel strategy ofcytosolically perturbing the CXCR2 PDZ-domain interaction of the macromolecular complex. This perturbation disrupts spatial sensation of a chemokine gradient, yet stillallows cells to mobilize actin and chemotax. Furthermore, I show CXCR2 PDZ-domainperturbation does not disrupt migration through bacterial derived chemoattractantreceptors.