Understanding and manipulating inflammatory cell trafficking is an ideal therapeutic target for patients with organ-specific autoimmune disease such as rheumatoid arthritis (RA). Chemokines and their receptors are critical mediators of leukocyte trafficking;however, the multiplicity of ligand-receptor binding poses a challenge when attempting to inhibit unwanted cellular migration toward inflammation. An ideal target is a downstream molecule that generalizes to multiple chemokine receptor interactions. Chemokine receptors are members of the large family of G-protein coupled receptors (GPCRs). G-protein receptor kinases (GRKs) phosphorylate the GPCR in an agonist-dependent fashion, and the subtypes 2, 3, 5, and 6 are most highly expressed in leukocytes. Previous studies from the Patel laboratory have shown that deficiencies in GRK6 or GRK2 affect the migration of leukocyte subsets in vitro and in vivo. What is not known is how inhibition of the GRK system would affect leukocyte trafficking and disease pathogenesis in inflammatory arthritis. Our long term goal is to identify novel therapeutic targets to treat patients with RA. The overall objective of this proposal is to understand the functional consequences of GRKs in leukocyte trafficking and disease expression in animal models of RA Based on previous studies and preliminary data, it is our central hypothesis that GRK6 and GRK2 are critical mediators of leukocyte migration in inflammatory arthritis. Using two different arthritis models in mice deficient in GRK6 or 2 allows us to study the effects of these molecules on both the acute and chronic forms of inflammation.
Our specific aims are as follows: 1. Characterize the acute inflammatory response in mice deficient in GRK6 or GRK2 after inducing arthritis using a passive transfer autoantibody model. 2. Characterize the chronic inflammatory response in mice deficient in GRK6 or GRK2 after arthritis is induced de novo by immunization with type II collagen. 3. Explore the extra-articular disease manifestations of mice deficient in GRK6 and GRK2. Relevance: This proposal intends to focus on GRKs downstream of the chemokine receptor since they generalize to multiple chemokine-receptor interactions. The effects of GRK inhibition in leukocyte migration and disease pathogenesis could lead to therapies that target GPCR signaling pathways in patients with RA.
