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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR059286-03
Application #
8514527
Study Section
Special Emphasis Panel (ZAR1-EHB (M1))
Program Officer
Mao, Su-Yau
Project Start
2011-08-08
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$70,300
Indirect Cost
$22,800
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Shah, Shaili; Wu, Eveline; Rao, V Koneti et al. (2014) Autoimmune lymphoproliferative syndrome: an update and review of the literature. Curr Allergy Asthma Rep 14:462
Brozowski, Jaime M; Billard, Matthew J; Tarrant, Teresa K (2014) Targeting the molecular and cellular interactions of the bone marrow niche in immunologic disease. Curr Allergy Asthma Rep 14:402
Todoric, Krista; Koontz, Jessica B; Mattox, Daniel et al. (2013) Autoimmunity in immunodeficiency. Curr Allergy Asthma Rep 13:361-70
Giguere, Patrick M; Billard, Matthew J; Laroche, Genevieve et al. (2013) G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis. Mol Immunol 54:193-8