Increased METTL3 expression and m6A RNA methylation may contribute to the development of dry eye in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder defined by xerostomia and keratoconjunctivitis sicca, and its etiology remains unknown. N6-methyladenosine (m6A) is the predominant posttranscriptional modification in eukaryotic mRNAs and is dynamically regulated by m6A regulators. Dysregulation of m6A modification is closely associated with several autoimmune disorders, but the role of m6A modification in pSS remains unknown. This study investigated the potential role of m6A and m6A-related regulators in pSS patients with dry eye.

Our work revealed that the upregulation of m6A and METTL3 was associated with the performance of serological indicators and dry eye signs in pSS patients with dry eye. METTL3 may contribute to the pathogenesis of dry eye related to pSS.

This cross-sectional study included forty-eight pSS patients with dry eye and forty healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) were isolated, and the level of m6A in total RNA was measured. The expression of m6A regulators was determined utilizing real-time PCR and western blotting. The serological indicators detected included autoantibodies, immunoglobulins (Igs), complement factors (Cs), and inflammatory indicators. Dry eye symptoms and signs were measured, including the ocular surface disease index, Schirmer's test (ST), corneal fluorescein staining score (CFS), and tear break-up time. Spearman's correlation coefficient was employed to assess the associations of m6A and m6A-related regulator expression with clinical characteristics.

The expression level of m6A was markedly increased in the PBMCs of pSS patients with dry eye compared to HCs (P value<0.001). The relative mRNA and protein expression levels of the m6A regulators methyltransferase-like 3 (METTL3) and YT521-B homology domains 1 were markedly elevated in pSS patients with dry eye (both P value<0.01). The m6A RNA level was found to be positively related to METTL3 expression in pSS patients (r = 0.793, P value<0.001). Both the m6A RNA level and METTL3 mRNA expression correlated with the anti-SSB antibody, IgG, ST, and CFS (all P values < 0.05). The m6A RNA level was associated with C4 (r = -0.432, P value = 0.002), while METTL3 mRNA expression was associated with C3 (r = -0.313, P value = 0.030). Conclusions: Our work revealed that the upregulation of m6A and METTL3 was associated with the performance of serological indicators and dry eye signs in pSS patients with dry eye. METTL3 may contribute to the pathogenesis of dry eye related to pSS.