Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis
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
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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Article Immunology

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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Histopathological and cellular responses in Ccr2–/– mice after induction...
Histopathological and cellular responses in Ccr2–/– mice after induction of CIA or peritonitis. (A) X-ray of the paw of a Ccr2–/– mouse, shown to provide anatomical orientation. The abbreviated names of the bones highlighted in B and C are given in parentheses. Histopathological evaluation of the joints were conducted after (B and C) H&E, (D and E) TRAP (for osteoclasts), and (F) orange G (for enhanced bone visualization) staining. Affected joints derived from WT mice (B and D) show relatively normal articular surfaces, intact joint spaces, and absence of significant periarticular inflammation. Ccr2–/– mice (C, E, and F) showed irregular articular surfaces, collapsed joint space, loss of cartilage, and an increase in connective tissue adjacent to the joint space with abundant osteoclasts stained red by TRAP stain. Representative joints collected 30 days after the second immunization are shown. Note that, at this time point, there was little visual evidence of arthritis in the WT mice and hence the relatively normal histopathology in these mice (see Figure 1B). (F and G) To determine the nature of the cell types recruited, FACS analysis was performed on cells derived from the inflamed joints of four mice from each group. (H) Number of macrophages in inflamed joints. (I) Number of peritoneal monocytes/macrophages 72 hours after thioglycollate injection. *P < 0.05; **P < 0.01. Data shown are representative of one of three experiments. In G–I, the white and black histograms refer to WT and Ccr2-null mice, respectively.