Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis
Marlon P. Quinones, … , William A. Kuziel, Seema S. Ahuja
Marlon P. Quinones, … , William A. Kuziel, Seema S. Ahuja
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):856-866. https://doi.org/10.1172/JCI20126.
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Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis

Abstract

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.

Authors

Marlon P. Quinones, Sunil K. Ahuja, Fabio Jimenez, Jason Schaefer, Edgar Garavito, Arun Rao, George Chenaux, Robert L. Reddick, William A. Kuziel, Seema S. Ahuja

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Figure 1

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CIA incidence and severity is increased in Ccr2–/– mice. The data shown ...
CIA incidence and severity is increased in Ccr2–/– mice. The data shown in this figure are representative of one of a minimum of three experiments. (A–F) In the experiment shown, Ccr2–/– mice (n = 8), Ccr5–/– mice (n = 6), and WT mice (n = 10) were given primary and booster injections of bovine CII and monitored two to three times per week for incidence and severity of arthritis. All mice were backcrossed six generations into the DBA/1J background. Days after immunization in A and B represent days after the second immunization with CII. (A) The cumulative number of arthritic animals in each group is shown as a percentage of the total number immunized with CII. (B) Arthritic score for each group at each time point was divided by the number of arthritic mice to calculate a mean severity score (± SEM). The maximal arthritic score for Ccr2–/– mice (11.0 ± 0.8) was significantly higher than the scores for WT (3.9 ± 0.7) and Ccr5–/– mice (3.2 ± 1.2) (P < 0.0001). The difference between WT and Ccr5–/– mice was not significant (P = 0.5). Photomicrographs (C and D) and radiographs (E and F) from WT and Ccr2–/– mice depicting severe arthritis and bone destruction and erosion in Ccr2–/– mice. (G) Incidence and (H) severity of arthritis determined 2 weeks after immunization with CII in F8 backcrossed Ccr2–/– (n = 3–4 mice per experiment) and WT mice (n = 3–4 mice per experiment).