Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis

Abstract

Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17<i>R</i>-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17<i>R</i>-RvD1 significantly reduced PGE₂ biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17<i>R</i>-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17<i>R</i>-RvD1 were abolished in RvD1 receptor-deficient mice termed <i>ALX/fpr2/3^-/-</i> . These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA.