Omega-3 PUFA supplementation promotes arthritis resolution by modulating joint cell phenotype involving E-series resolvins

Abstract The cellular mechanisms of omega-3 polyunsaturated fatty acid (ω3 PUFA) supplementation were investigated in inflammatory arthritis. Mice fed a prophylactic ω3 PUFA-enriched diet displayed reduced arthritis and paw oedema, with a discrete regulation of innate and stromal cell phenotypes in arthritic joints. Non-classical monocytes and VCAM-1 + synovial fibroblasts were lower at peak arthritis while pro-resolution MerTK + CD206 + macrophages were increased at resolution onset. Lipid mediator profiling of arthritic paws identified a distinct repertoire of molecules in ω3-fed mice, with elevated EPA-derived resolvin E2 (RvE2) and RvE4, compared with increased TXB 2 and PGF 2α with a normal diet. Pharmacological treatment of mice with RvE2 and RvE4 concomitant with arthritis induction, attenuated arthritis and increased MerTK + CD206 + macrophages in arthritic joints. Synovial explant treatment revealed reduced pro-inflammatory mediator and enzyme release including IL-6, CCL2 and MMP-9. In arthritic patient blood, RvE2 and RvE4 (100 nM) lowered monocyte ICAM-1 expression. Collectively, these data identify cellular and molecular determinants of an ω3 diet in pre-clinical and human settings, highlighting therapeutic potential.