Open Access Thesis
Date of Award
Biochemistry and Molecular Biology
Neutrophils are the body's first responders to inflammation, being the most abundant white blood cell type in circulation and they quickly initiate an immune response through chemokine signaling. Inflammatory chemokines signal via their receptor CXCR2, which initiates an inflammatory response, recruiting leukocytes to sites of inflammation. Chemokine signaling is important for proper host protection, yet uncontrolled activity is responsible for a variety of pathological conditions: including rheumatoid 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 in neutrophils, containing NHERF1 and PLCβ2. I also demonstrate a novel strategy of cytosolically perturbing the CXCR2 PDZ-domain interaction of the macromolecular complex. This perturbation disrupts spatial sensation of a chemokine gradient, yet still allows cells to mobilize actin and chemotax. Furthermore, I show CXCR2 PDZ-domain perturbation does not disrupt migration through bacterial derived chemoattractant receptors.
Castelvetere, Marcello, "Disrupting cxcr2 macromolecular complex pdz-domain interactions during inflammatory chemotaxis" (2012). Wayne State University Theses. Paper 172.