Granulocyte chemotaxis and disease expression are differentially regulated by GRK subtype in an acute inflammatory arthritis model (K/BxN)

Duke University, Department of Medicine, Division of Cardiology, Durham, NC 27110, USA
Clinical Immunology (Impact Factor: 3.67). 10/2008; 129(1):115-122. DOI: 10.1016/j.clim.2008.06.008


Chemokine receptors are G-protein coupled receptors (GPCRs) phosphorylated by G-protein receptor kinases (GRKs) after ligand-mediated activation. We hypothesized that GRK subtypes differentially regulate granulocyte chemotaxis and clinical disease expression in the K/BxN model.Methods
Clinical, histologic, and cytokine responses in GRK6−/−, GRK5−/−, GRK2+/−, and wildtype mice were evaluated using K/BxN serum transfer. Granulocyte chemotaxis was analyzed by transendothelial migration assays.ResultsBoth GRK6−/− and GRK2+/− mice had increased arthritis disease severity (p < 0.001); whereas GRK5−/− was not different from controls. Acute weight loss was enhanced in GRK6−/− and GRK2+/− mice (p < 0.001, days 3–10). However, GRK6−/− mice uniquely had more weight loss (> 10%), elevated serum IL-6, and enhanced migration toward LTB4 and C5a in vitro.ConclusionsGRK6 and -2, but not GRK5, are involved in the pathogenesis of acute arthritis in the K/BxN model. In particular, GRK6 may dampen inflammatory responses by regulating granulocyte trafficking toward chemoattractants.

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Available from: Teresa K Tarrant, Sep 22, 2014
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    • "GRK6 typically has a negative regulatory role in CXCR4 activation and CXCL12-induced cell migration [24,26]. For example, GRK6 deficiency is associated with impaired desensitization and enhanced CXCR4-mediated neutrophil migration and has been implicated in the pro-inflammatory response seen in rheumatoid arthritis [26,36]. However, in HeLa cells, siRNA-based functional screening identified GRK6 as a critical positive regulator of integrin-mediated cell adhesion and migration [37]. "
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    • "Chemotaxis experiments were performed as described (Tarrant et al., 2008) on Ly6C-enriched splenocytes. Briefly, mouse spleens were manually disrupted and filtered through 70 ␮m mesh, RBCs lysed, and enriched for Ly6C+ cells by magnetic separation using anti-Ly6C-biotin beads (Miltenyi Biotec, MA). "
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