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 4

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Higher accumulation of activated T and B cells in vivo, and decreased AI...
Higher accumulation of activated T and B cells in vivo, and decreased AICD in vitro in Ccr2–/– mice. (A) Quantitative analysis of proliferation and apoptosis of WT or Ccr2-null splenocytes derived from naive mice after stimulation with anti-CD3. carboxy-fluorescein succinimidyl ester–labeled (CFSE-labeled) splenocytes from WT and Ccr2–/– mice were stimulated with soluble anti-CD3 antibody (2 μg/ml), and cellular proliferation was assessed by FACS after 72 hours. CFSE-labeled cells were also stained for CD4 and Annexin V, and the percentage of CD4+AnnexinV+ cells in each cell division was determined. The number of generations is noted in the upper left of each panel. Data shown in this panel are representative of at least three separate experiments derived from two animals per group. Single-cell suspensions were prepared from arthritic joints DLN derived from WT or Ccr2–/– mice 30 days after the second immunization with CII. Cell numbers (B) and activation markers on T and B cells (C and D) in the DLN of WT and Ccr2–/– mice are depicted. The cells were counted and stained with the fluorescent-labeled Ab’s shown in B and C. In D, the percentage of activated T cells (CD4+/CD44+) or (CD4+/RANKL+) or B cells (B220+/CD86+) within the total T or B cell population is shown. The findings shown in A–C are representative of three separate experiments, and the data depicted are from three WT and five Ccr2–/– mice.