MYSM1 expression in monocytes is negatively correlated to disease activity in Rheumatoid Arthritis, which may be related to the inhibitory effect on inflammatory aging

Abstract

Objective: Inflammatory aging is a key contributor to the onset and progression of rheumatoid arthritis (RA). The deubiquitinase Myb-like, SWIRM, and MPN domain-containing protein 1 (MYSM1) is known to play a crucial role in DNA damage repair and inflammatory aging, however, the precise mechanisms by which it exerts these effects remain unclear. This study aimed to investigate the relationship between MYSM1 expression in peripheral blood mononuclear cells (PBMCs) and DNA damage-induced inflammatory aging in RA patients, elucidating its potential role in RA pathogenesis.

Methods: PBMCs were isolated from RA patients and age-matched healthy controls. MYSM1 mRNA expression was quantified using qPCR, and its association with RA disease activity and clinical parameters was evaluated. Bead-based sorting was used to purify PBMC subsets, followed by quantitative PCR (qPCR), Western blotting, and immunofluorescence to validate DNA damage-associated aging phenotypes in RA monocytes. Furthermore, a DNA damage-induced senescence model was established by treating THP-1 cells with bleomycin in vitro. Cell proliferation assays, Western blotting, and transcriptomic analysis were performed to explore changes in MYSM1 expression and its correlation with aging-related signaling pathways.

Results: Compared with healthy controls, RA patients showed significantly reduced MYSM1 expression in PBMCs, which was inversely correlated with both disease activity and TNF-α levels. Subset analysis of immune cells revealed significant downregulation of MYSM1 in RA monocytes, accompanied by cytoplasmic dsDNA accumulation and the emergence of a γH2AX-mediated aging phenotype. These alterations triggered activation of inflammatory signaling pathways and the release of senescence-associated secretory phenotype (SASP) factors, aggravating RA pathology. Similarly, in the bleomycin-induced in vitro model, MYSM1 expression was suppressed during DNA damage-driven inflammatory aging, and senescent monocytes displayed features of inflammatory aging, including aberrant immune pathway activation.

Conclusions: Decreased MYSM1 expression in RA monocytes may be associated with compromised DNA damage repair, cytoplasmic dsDNA accumulation, γH2AX-related cellular aging, and subsequent activation of inflammatory signaling and SASP release. These results suggest that MYSM1 downregulation may contribute to inflammatory aging and is closely associated with the development and progression of rheumatoid arthritis. Key Points • MYSM1 expression is reduced in PBMCs from patients with rheumatoid arthritis and is inversely associated with disease activity and TNF-α levels. • Decreased MYSM1 in RA monocytes may be associated with impaired DNA damage repair, cytoplasmic dsDNA accumulation, cellular senescence, and enhanced release of pro-inflammatory senescence-associated secretory phenotype (SASP) factors.

Keywords: Inflammatory aging; Myb-like, SWIRM, and MPN domain-containing protein 1; Rheumatoid Arthritis; Senescence-associated secretory phenotype.