G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses.
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.
1.CB #7280, 3300 Manning Dr., Chapel Hill, NC 27599, USA. tarra002@med.unc.edu.
Teresa K
TK
Tarrant
Matthew J
MJ
Billard
Roman G
RG
Timoshchenko
Marcus W
MW
McGinnis
D Stephen
DS
Serafin
Oded
O
Foreman
Denise A
DA
Esserman
Nelson J
NJ
Chao
William E
WE
Lento
David M
DM
Lee
Dhavalkumar
D
Patel
David P
DP
Siderovski
D000818:Animals; D002461:Cell Line, Transformed; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006098:Granulocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014860:Warts / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D054770:G-Protein-Coupled Receptor Kinase 3; C517850:GRK3 protein, mouse
arthritis; chemokine receptor; granulocytes; hematopoiesis