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.Nonstandard abbreviations used: activation-induced cell death (AICD); alkaline phosphatase (AKP); antigen (Ag); chemokine receptor (CCR); collagen Ab-induced arthritis (CAIA); collagen-induced arthritis (CIA); draining lymph nodes (DLN); graft-versus-host-disease (GVHD); macrophage inflammatory protein (MIP); monocyte chemoattractant protein (MCP); p-nitrophenyl phosphate (pNPP); receptor activator NF-κB ligand (RANKL); rheumatoid arthritis (RA); rheumatoid factor (RF); ribonuclease protection assay (RPA); single-stranded DNA (ssDNA); tartrate-resistant acid phosphatase (TRAP); type II collagen (CII).
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.Nonstandard abbreviations used: activation-induced cell death (AICD); alkaline phosphatase (AKP); antigen (Ag); chemokine receptor (CCR); collagen Ab-induced arthritis (CAIA); collagen-induced arthritis (CIA); draining lymph nodes (DLN); graft-versus-host-disease (GVHD); macrophage inflammatory protein (MIP); monocyte chemoattractant protein (MCP); p-nitrophenyl phosphate (pNPP); receptor activator NF-κB ligand (RANKL); rheumatoid arthritis (RA); rheumatoid factor (RF); ribonuclease protection assay (RPA); single-stranded DNA (ssDNA); tartrate-resistant acid phosphatase (TRAP); type II collagen (CII).
The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6→bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4+ T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-γ-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4+ T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2−/− CD4+ T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4+ T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2−/− splenocyte→bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.
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