Background/Purpose: The nuclear factor-kappaB (NF-kB) activation plays a pivotal role and macrophages are of central importance in the pathogenesis of rheumatoid arthritis (RA). The SirT1, which is a class III histone deacetylase, deacetylates acetyl group of various transcription factors including NF-kB and modulates their functions, suggesting that myeloid deletion of SirT1 may affect inflammatory arthritis such as RA. The study was performed to assess the function of SirT1 in inflammation and joint destruction in in vivo model of RA.

Methods: The mice with myeloid cells-specific deletion of SirT1 (M-SirT1 KO) were generated by using the loxP/Cre recombinase system. K/BxN serum transfer arthritis was induced in M-SirT1 KO mice and their age-matched littermate loxP controls (Sirt1^loxP/loxPLysM-Cre^-/-) by injection of K/BxN serum. Arthritis severity was assessed by clinical and histopathologic scoring. The levels of inflammatory cytokines in the joints and serum were measured by ELISA. The NF-kB acetylation, activation, and cytokine/chemokine expression were assessed by Western, EMSA, and ELISA, respectively, using bone marrow-derived macrophages (BMMs).

Results: M-SirT1 KO showed severe form of inflammatory arthritis accompanied by aggravated histopathologic findings including synovial inflammation, bone erosion, and cartilage damage. These effects were paralleled by increased F4/80+ macrophage infiltration into synovium and increased levels of IL-1, IL-6, and RANKL. TNF-α stimulated M-SirT1 KO BMMs displayed hyperacetylated p65 and increased NF-kB binding activity than controls, resulting in increased transcriptional activation of proinflammatory target genes.

Conclusion: This study demonstrates that SIRT1, in macrophages, functions to inhibit NF-kB-mediated transcription, implying that myeloid cell-specific modulation of SirT1 may be beneficial in the treatment of inflammation arthritis such as RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/myeloid-deletion-of-sirt1-aggravates-inflammatory-arthritis-via-nuclear-factor-kappab-activation-in-animal-model-of-rheumatoid-arthritis/