Background/Purpose:   Chemokine receptors are G Protein Coupled Receptor (GPCR) family members that direct cell migration, differentiation, and survival in inflammatory conditions, but neutralization strategies have had mixed results in autoimmunity and even less efficacy in Rheumatoid Arthritis (RA). This has been partially attributed to chemokine receptor/ligand redundancy in inflammation, and it has been proposed that a regulator of GPCR signaling should be targeted rather than neutralization of singular chemokines or their receptors.  G protein coupled receptor kinase 3 (GRK3) activity negatively regulates GPCR activation, but also helps recruit downstream signaling machinery to coordinate leukocyte responses. GRK3-deficient mice were previously shown to be protected from disease in two acute models of inflammatory arthritis (K/BxN serum transfer and Collagen Antibody Induced Arthritis) by altering granulocyte migration and innate responses.  In this study, we examine the effects of GRK3 knockdown in the chronic, HLA-restricted Collagen Induced Arthritis (CIA) model.

Methods:   The Collagen-Induced Arthritis (CIA) model of inflammatory arthritis was used to test in vivo disease progression in GRK3-deficient DBA mice.  To examine the biological basis for protection in GRK3 knockout mice, an interdisciplinary approach was used.  Traditional migration and survival assays were performed on leukocytes ex vivo and a mathematical model of GRK3 signal regulation was developed.

Results:   Results showed that GRK3-deficient DBA mice are protected from developing CIA in vivo. Serum antibody is decreased in GRK3-deficient mice and PCR of the joint revealed greatly reduced levels of IL-17, IL-23, TNFα, and IL-1β transcript expression, suggesting a lack of inflammatory cell infiltration. Ex vivo assays describe altered migration and survival of immune cells.  A mathematical model was created to further examine and test the mechanisms of signal regulation.

Conclusion: Proinflammatory functions of leukocytes critical to RA development require GRK3 function. Having a single protein target for RA therapeutic intervention that appears to selectively prevent infiltration into the joint represents a compelling target for therapeutic attempts at single cytokine or chemokine neutralization.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/g-protein-coupled-receptor-kinase-3-regulation-of-inflammatory-arthritis/