Myeloid sirtuin 6 deficiency accelerates experimental rheumatoid arthritis by enhancing macrophage activation and infiltration into synovium

Background: We recently reported that myeloid sirtuin 6 (Sirt6) is a critical determinant of phenotypic switching and the migratory responses of macrophages. Given the prominent role of macrophages in the pathogenesis of rheumatoid arthritis (RA), we tested whether myeloid Sirt6 deficiency affects the development and exacerbation of RA. Methods: Arthritis was induced in wild type and myeloid Sirt6 knockout (mS6KO) mice using collagen-induced and K/BxN serum transfer models. Sirt6 expression (or activity) and inflammatory activities were compared in peripheral blood mononuclear cells (PBMCs) and monocytes/macrophages obtained from patients with RA or osteoarthritis. Findings: Based on clinical score, ankle thickness, pathology, and radiology, arthritis was more severe in mS6KO mice relative to wild type, with a greater accumulation of macrophages in the synovium. Consistent with these findings, myeloid Sirt6 deficiency increased the migration potential of macrophages toward synoviocyte-derived chemoattractants. Mechanistically, Sirt6 deficiency in macrophages caused an inflammation with increases in acetylation and protein stability of forkhead box protein O1. Conversely, ectopic overexpression of Sirt6 in knockout cells reduced the inflammatory responses. Lastly, PBMCs and monocytes/macrophages from RA patients exhibited lower expression of Sirt6 than those from patients with osteoarthritis, and their Sirt6 activity was inversely correlated with disease severity. Interpretation: Our data identify a role of myeloid Sirt6 in clinical and experimental RA and suggest that myeloid Sirt6 may be an intriguing therapeutic target. Fund: Medical Research Center Program and Basic Science Research Program through the National Research Foundation of Korea.