Targeting the function of extracellular cyclophilins as a novel approach for the treatment of Rheumatoid Arthritis (RA). (35.13)

Abstract

Elevated levels of extracellular cyclophilins A and B are present in the synovial fluid of RA patients and have been reported to correlate with disease severity. Based on the findings that cyclophilins have potent chemotactic properties for various subsets of pro-inflammatory leukocytes, we propose that extracellular sources of cyclophilins may contribute to the development of RA pathology by promoting leukocyte recruitment into synovial spaces and tissues. Using the collagen-induced arthritis (CIA) mouse model of RA, we tested the impact of treating CIA mice with non immunosuppressive analogs of cyclosporine A (CsA) to inhibit the function of cyclophilins. Our findings demonstrate that treatment with non-immunosuppressive CsA leads to a significant reduction in CIA clinical disease severity, with corresponding reductions in histopathology and levels of pro-inflammatory cytokines and enzymes within the joints. Inhibiting the function of cyclophilin A might provide a novel approach for reducing RA-mediated joint inflammation.