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


RESULTS
Both 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.


CONCLUSIONS
GRK6 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.
Tarrant
Teresa K
TK
Thurston Arthritis Research Center, Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. tarra002@med.unc.edu
Rampersad
Rishi R
RR
Esserman
Denise
D
Rothlein
Lisa R
LR
Liu
Peng
P
Premont
Richard T
RT
Lefkowitz
Robert J
RJ
Lee
David M
DM
Patel
Dhavalkumar D
DD
D000208:Acute Disease; D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D006098:Granulocytes / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007975:Leukotriene B4 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D015850:Interleukin-6; D007975:Leukotriene B4; D015936:Complement C5a; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6