Downregulated YTHDF2 expression in systemic lupus erythematosus is associated with inflammatory and neutrophil cytokine production.

Objectives: An increasing body of evidence suggests that N6-methyladenosine (m6A) plays a crucial role in the etiology of SLE. We focused on YTHDF2 expression in neutrophils and the relationship between YTHDF2 and the pathogenesis of SLE.

Methods: Sixty-one patients with SLE and 48 healthy controls (HC) were recruited, and their clinical characteristics were recorded. The mRNA levels of m6A "writers" (METTL3, METTL14, WTAP), "erasers" (FTO and ALKBH5), "readers" (YTHDF2), and inflammatory factors (interleukin-1β, interleukin-6, interleukin-8, and TNF-α) in neutrophils were determined by reverse transcription-quantitative PCR. The protein of YTHDF2 was determined by Western blotting. The correlations between the YTHDF2 in neutrophils of SLE patients and clinical features were examined by Spearman's method. YTHDF2 and TNF-α expression in neutrophils were examined after stimulation by SLE serums.

Results: The mRNA expression of YTHDF2 in neutrophils was significantly decreased, and the protein level of YTHDF2 in neutrophils was decreased. The mRNA expression of YTHDF2 in neutrophils correlated with L% (r = 0.5796, P < 0.0001), LMR (r = 0.3524, P = 0.0062), WBC (r =  - 0.3186, P = 0.0123), N (r =  - 0.4141, P = 0.0010), N% (r =  - 0.4813, P < 0.0001), NLR (r =  - 0.5301, P < 0.0001), dNLR (r =  - 0.4945, P < 0.0001), and SII (r =  - 0.3930, P = 0.0019), which were suggested as the inflammatory conditions of SLE. In addition, the mRNA expression of TNF-α in neutrophils was significantly increased in SLE patients. Further analysis revealed that the mRNA expression of YTHDF2 in neutrophils was inversely correlated with TNF-α in SLE. Neutrophils from health control were significantly downregulated in their YTHDF2 expression and upregulated in their TNF-α expression following stimulation by serum from SLE patients.

Conclusion: This study indicates that the levels of YTHDF2 in peripheral blood neutrophils may be involved in the pathogenesis of SLE and could be a novel target for diagnosis and therapy. Key points • The mRNA expression of YTHDF2 in neutrophils of SLE and described that decreased mRNA of YTHDF2 in neutrophils correlated with L%, LMR, WBC, N, N%, NLR, dNLR, and SII. • The mRNA expression of TNF-α in neutrophils was significantly increased and correlated with YTHDF2 in SLE patients. • Neutrophils from health control were significantly downregulated in their YTHDF2 expression and upregulated in their TNF-α expression following stimulation by serum from SLE patients.