METTL14 Declines Th17/Treg Ratio Via the m6A Modification of DUSP23 to Alleviate Systemic Lupus Erythematosus

The imbalance between T helper (Th) 17 cells and regulatory T (Treg) cells is involved in the progression of systemic lupus erythematosus (SLE). Dual-specificity protein phosphatase 23 (DUSP23) expression is elevated in CD4+ T cells from SLE patients, though its function role remains unclear. Peripheral blood mononuclear cells (PBMCs), serum, and CD4+ T cells were isolated from blood samples of SLE patients. MRL/lpr mice were used to investigate the role of METTL14 in vivo. The expression of methyltransferase-like 14 (METTL14) and DUSP23 in cells was determined by RT-qPCR or immunoblotting. The proportions of Th17 and Treg cells were primarily determined by flow cytometry. The expression of key transcription factors and the secretion of related cytokines were evaluated by immunoblotting or ELISA. MeRIP was performed to assess the m6A modification of DUSP23 mRNA. DUSP23 is elevated in PBMCs from SLE patients. Inhibition of DUSP23 reduced Th17 but increased Treg cells proportions within CD4+ T cells in vitro. A negative correlation was observed between DUSP23 and METTL14 expression in SLE-derived PBMCs. Mechanistically, METTL14 enhanced the m6A modification of DUSP23 mRNA, thereby promoting its decay. In MRL/lpr mice, METTL14 overexpression reduced Th17/Treg imbalance and ameliorated renal injury. The results demonstrate that METTL14 ameliorates murine SLE by attenuating the Th17/Treg imbalance through m6A-mediated decay of DUSP23, providing novel insights for SLE diagnosis and therapy. The level of DUSP23 is up-regulated in PBMCs from SLE patients. Knockdown of DUSP23 restores the balance of Th17/Treg cells in vitro. METTL14 reduces the mRNA stability of DUSP23 by modulating its m6A modification. METTL14 restores the balance of Th17/Treg cells and the damage of renal tissue in MRL/lpr mice via inhibiting DUSP23.