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Published on: November 9, 2018
G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory
Teresa K Tarrant1, Matthew J Billard, Roman G Timoshchenko
11.CB #7280, 3300 Manning Dr., Chapel Hill, NC 27599, USA. tarra002@med.unc.edu.
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.
Insights
Loss of GRK3 impairs chemokine receptor regulation, mimicking some WHIM syndrome features. GRK3 deficiency protects against inflammatory arthritis by altering granulocyte migration.
Area of Science:
- Immunology and Molecular Biology
- Cellular Signaling and Inflammation
Background:
- Chemokine receptor signaling is crucial for leukocyte migration during inflammation.
- G protein-coupled receptor kinases (GRKs) regulate chemokine receptor desensitization.
- GRK3 deficiency is linked to WHIM syndrome, a human immunodeficiency disorder.
Purpose of the Study:
- To investigate the role of GRK3 in regulating CXCL12/CXCR4 signaling.
- To characterize the phenotype of GRK3 knockout mice.
- To evaluate the therapeutic potential of GRK3 inhibition in inflammatory arthritis.
Main Methods:
- Generation and analysis of GRK3 knockout (GRK3-/-) mice.
- Assessment of CXCL12/CXCR4 signaling, including desensitization and ERK activation.
- Evaluation of leukocyte migration and counts in blood and bone marrow.
- Testing GRK3-/- mice in acute inflammatory arthritis models (K/BxN serum transfer and CAIA).
Main Results:
- GRK3-/- mice display impaired CXCL12-mediated desensitization and enhanced CXCR4 signaling.
- These mice exhibit altered granulocyte migration, reduced circulating granulocytes, and protection from inflammatory arthritis.
- GRK3-/- mice show features distinct from WHIM syndrome, including leukocytosis and minimal hypogammaglobulinemia.
Conclusions:
- GRK3 is a key regulator of CXCL12/CXCR4 signaling, and its absence partially recapitulates WHIM syndrome.
- GRK3 deficiency protects against granulocyte-dependent inflammatory arthritis via altered leukocyte trafficking.
- Targeting GRK3 may offer a therapeutic strategy for inflammatory arthritis.
