G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses

Abstract

Chemokine receptor interactions coordinate leukocyte migration in inflammation. Chemokine receptors are GPCRs that when activated, are phosphorylated by GRKs to turn off G protein-mediated signaling yet recruit additional signaling machinery. Recently, GRK3 was identified as a negative regulator of CXCL12/CXCR4 signaling that is defective in human WHIM syndrome. Here, we report that GRK3-/- mice exhibit numerous features of human WHIM, such as impaired CXCL12-mediated desensitization, enhanced CXCR4 signaling to ERK activation, altered granulocyte migration, and a mild myelokathexis. Moreover, GRK3-/- protects mice from two acute models of inflammatory arthritis (K/BxN serum transfer and CAIA). In these granulocyte-dependent disease models, protection of GRK3-/- mice is mediated by retention of cells in the marrow, fewer circulating granulocytes in the peripheral blood, and reduced granulocytes in the joints during active inflammation. In contrast to WHIM, GRK3-/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia. Thus, we conclude that the loss of GRK3-mediated regulation of CXCL12/CXCR4 signaling contributes to some, but not all, of the complete WHIM phenotype and that GRK3 inhibition may be beneficial in the treatment of inflammatory arthritis.

Role of G protein-coupled receptor kinases in cell migration

“…Comparison of GRKs knockout mice in an acute inflammatory arthritis model indicated a role for GRK2, GRK3 and GRK6, but not GRK5, in granulocyte migration in such conditions [31,32].…”

Functional Consequences of Perturbed CXCL12 Signal Processing: Analyses of Immature Hematopoiesis in GRK6-Deficient Mice

“…Therefore, similar expression levels of GRKs 2, 3, and 4 as of GRK6 in HSPCs were unexpected. Slightly upregulated expression of GRK3 might suggest partial compensatory upregulation given the very recently reported role of GRK3 for immature hematopoiesis [52]. The observed robust signaling perturbance in GRK6…”

G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

“…This was seen in response to activation of a variety receptors including the β2-adrenergic receptor, cannabinoid receptor-2 (Franklin & Carrasco, 2013), angiotensin 1A receptor (Daniela Sorriento et al, 2008) and the insulin-like growth factor-1 receptor (Zheng et al, 2012). In support of this, bone marrow-derived leukocytes from GRK3 knockout mice exhibit enhanced ERK1/2 expression in response to CXCL12 (Tarrant et al, 2013). GRK3 can also interact with and modulate these pathways and so further study in this area is necessary to fully understand the regulatory capabilities of this GRK on these pathways.…”