P063/O11 Inhibition of arginase-1 expression by the transcription factor Fra-1 in macrophages exacerbates rheumatoid arthritis inflammation

Career situation of first and presenting author Student for a master or a PhD. Introduction The activator protein (AP)-1 transcription factor family, especially its subfamily of FOS proteins (cFos, FosB, Fra-1 and Fra-2) are associated to the regulatory network of macrophage responses. Moreover, it is well known that macrophages are central player during rheumatoid arthritis (RA). Objectives This study aims to delineate the role of Fra-1 in macrophages during the acute destructive inflammatory phase of RA. Methods Therefore, we applied the serum-induced arthritis (K/BxN) model to Fra-1 deficient mice controlled by the Mx1 promoter (Fra-1 ΔMx ) or the LysM promoter (Fra-1 ΔLysM ). Moreover, we performed in vitro analyses of macrophage polarization in wildtype and Fra-1 deficient macrophages, as well as micro-arrays and ChIP sequencing analyses to delineate Fra-1 targets in activated macrophages. We completed our analysis by studying Fra-1 expression in RA patients’ synovium. Results Fra-1 mutant mice had decreased arthritis severity compared to their littermate wildtype mice. The alleviated arthritis was accompanied to increased arginase-1 (Arg1) expression and activity in the joints, suggesting that its anti-inflammatory features milder RA inflammation. Sorting of immune cell populations revealed macrophages as the major source of Arg1, which was increased in Fra-1 mutant mice. Mechanistically, Fra-1 transcriptionally inhibited Arg1 expression in macrophages. Moreover, inhibition of Arginase in Fra-1 mutant mice restored a full blunt inflammatory RA response and the supplementation of mice with l-arginine, leading to increased arginase activity in the joint, is sufficient to milder arthritis. Synovium histological sections from RA patients showed a correlation between Arg1, Fra-1 and the DAS28 score, confirming that increased Arg1 activity is of benefit also for human inflammatory joint disease. Conclusions Our data show for the first time that Fra-1 is a pivot between pro- and anti-inflammatory macrophage. By inhibiting Arg1 activity, Fra-1 exacerbates RA inflammation and joint destruction. Disclosure of Interest None declared.