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CD8?? dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice.

ABSTRACT:

Objective

Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3? regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGF?-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2?/?) mice had impaired DCs migration and reduced CD8?? DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2?/? mice, we tested the hypothesis that CD8?? DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8?? DCs in Ccr2?/? and SKG mice.

Methods

To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8?? DCs.

Results

Flt3L-mediated expansion of endogenous CD8?? DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8?? DCs ameliorated arthritis in Ccr2?/? mice and enhanced TGF?1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype.

Conclusion

CD8?? DCs were tolerogenic to the development of arthritis. CD8?? DCs deficiency heightened the sensitivity to arthritis in Ccr2?/? mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2?/? mice was T cell-independent.

SUBMITTER: Ibarra JM

PROVIDER: S-EPMC3426926 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Publications

CD8α⁺ dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice.

Ibarra Jessica M JM Quinones Marlon P MP Estrada Carlos A CA Jimenez Fabio F Martinez Hernan G HG Ahuja Seema S SS

Immunobiology 20110407 9

<h4>Objective</h4>Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3⁺ regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 de ...[more]

PMID: 21531476

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Project description:IntroductionProperdin amplifies the alternative pathway of complement activation. In the present study, we evaluated its role in the development of collagen antibody-induced arthritis (CAIA).MethodsArthritis was induced by intraperitoneal injection of a collagen antibody cocktail into properdin-deficient (KO) and wild-type (WT) C57BL/6 mice. Symptoms of disease were evaluated daily. The degree of joint damage was assessed histologically and with immunostaining for bone-resorption markers. Phenotypes of cell populations, their receptor expression, and intracellular cytokine production were determined with flow cytometry. Osteoclast differentiation of bone marrow (BM) precursors was evaluated by staining for tartrate-resistant acid phosphatase (TRAP).ResultsProperdin-deficient mice developed less severe CAIA than did WT mice. They showed significantly improved clinical scores and downregulated expression of bone-resorption markers in the joints at day 10 of disease. The frequencies of Ly6G?CD11b? cells were fewer in BM, blood, and synovial fluid (SF) of KO than of WT CAIA mice. The receptor activator of nuclear factor ?B ligand (RANKL) was downregulated on arthritic KO neutrophils from BM and the periphery. Decreased C5a amounts in KO SF contributed to lower frequencies of CD5aR?-bearing neutrophils. In blood, surface C5aR was detected on KO Ly6G? cells as a result of low receptor engagement. Circulating CD4? T cells had an altered ability to produce interleukin (IL)-17 and interferon (IFN)-? and to express RANKL. In KO CAIA mice, decreased frequencies of CD4? T cells in the spleen were related to low CD86 expression on Ly6GhighCD11b? cells. Arthritic KO T cells spontaneously secreted IFN-? but not IL-17 and IL-6, and responded to restimulation with less-vigorous cytokine production in comparison to WT cells. Fewer TRAP-positive mature osteoclasts were found in KO BM cell cultures.ConclusionsOur data show that the active involvement of properdin in arthritis is related to an increased proinflammatory cytokine production and RANKL expression on immune cells and to a stimulation of the RANKL-dependent osteoclast differentiation.