Chemokine-receptor interactions coordinate leukocyte migration in homeostatic and diseased states and are essential in the maintenance of a normal functioning immune system. Chemokine receptors are G-protein coupled receptors (GPCRs) phosphorylated by G-protein receptor kinases (GRKs), which serve as negative regulators to turn off GPCR signaling. Although most chemokine receptors have multiple ligands, CXCR4 is unique in its monogamous relationship with CXCL12 (SDF-1). Recently, it has been discovered that only one GRK isoform, GRK3, serves as a unique regulator of CXCL12/CXCR4 interactions in humans. From genetically engineered GRK3-deficient mice, we have found delayed CXCR4 internalization, increased CXCR4 responsiveness to CXCL12 by chemotaxis, and importantly, protection in two inflammatory arthritis models (serum transfer K/BxN and collagen induced arthritis). CXCR4 and GRK3 are expressed in both myeloid- and lymphoid-derived cells, which are important mediators of the inflammatory processes leading to disease in human rheumatoid arthritis (RA). This proposal plans to examine the effects of GRK3 targeted deletion on CXCR4, other chemokine receptors, myeloid cell trafficking and function, and lymphocyte trafficking and function, all of which are important to fully understand the implications of GRK3 in autoimmunity and as a potential therapeutic target for patients with RA.
This proposal intends to focus on G protein coupled receptor kinases (GRKs), which are regulators of chemokine receptors and leukocyte migration, in inflammatory arthritis disease models. Specifically, the effects of GRK3 inhibition on CXCR4/CXCL12 signaling and leukocyte migration could lead to therapies that target this signaling pathway in patients with rheumatoid arthritis.
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