Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis.
The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2-/- mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.
Quinones
Marlon P
MP
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Texas, USA.
Ahuja
Sunil K
SK
Jimenez
Fabio
F
Schaefer
Jason
J
Garavito
Edgar
E
Rao
Arun
A
Chenaux
George
G
Reddick
Robert L
RL
Kuziel
William A
WA
Ahuja
Seema S
SS
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology; D006801:Humans; D051379:Mice; D023421:Models, Animal; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D024043:Collagen Type II; D054390:Receptors, CCR2; D019707:Receptors, Chemokine