Background/Purpose: Annexin A1 (AnxA1) is recognized as an endogenous anti-inflammatory molecule. An AnxA1 receptor, formyl-peptide receptor 2 (FPR2), has been identified in human and mice. The contribution of FPR2 to rheumatoid arthritis (RA) is not well understood. We investigated the contribution of AnxA1 and FPR2 to the regulation of inflammatory arthritis.

Methods: Arthritis was induced by injection of K/B×N serum (38μl/mouse, ip) in wild-type or AnxA1-/- mice at day 0 and 2. Wild-type mice were treated with Compound 43, an agonist of FPR1/2, at 6-30μg/g on days 0 – 4. RA synovial like fibroblasts (FLS) were treated with FPR2 ligand or antagonist compounds, and AnxA1 was silenced using siRNA.

Results: Deficiency of AnxA1 significantly increased arthritis clinical and histopathological severity. Treatment of wild-type mice with Compound 43 dose-dependently and significantly suppressed clinical scores (Fig 1A), paw thickness (Fig 1B) and histopathologic severity. AnxA1 silencing increased RAFLS proliferation, ERK and NFKB activation. RAFLS expressed FPR2, and an FPR ligand inhibited proliferation while, blocking FPR2 significantly increased proliferation, ERK and NF-κB activation, and IL-6 release.

Conclusion: Compound 43 was potently therapeutic in K/BxN arthritis and FPR2 regulates RAFLS activation. These data suggest that FPR2 ligands may have important beneficial actions on RA.