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  • mRNA methylation controls salivary gland epithelial cell function and has a protective role in Sjögren’s disease

mRNA methylation controls salivary gland epithelial cell function and has a protective role in Sjögren’s disease

18 Sept 2024Annals of the Rheumatic Diseases

DOI : 10.1136/ard-2024-226224

Authors

Frederic Truffinet, Alejandro Arco-Hierves, Hosnia Shalabi, Juliette Pascaud, Paul Mazet, Elodie Rivière, Sacha E Silva-Saffar, Lucilla Fabbri, Sophie Leboucher, Laetitia Besse, Cedric Messaoudi, Aurore Attina, Alexandre David, Stephan Vagner, Gaetane Nocturne, Xavier Mariette, Rami Bechara

Abstract

Objectives

The RNA epitranscriptomic modification known asN6-methyladenosine (m6A) represents a novel mechanism of gene regulation that is poorly understood in human autoimmune diseases. Our research explores the role of this RNA m6A modification in salivary gland epithelial cells (SGEC) and its impact on the pathogenesis of Sjögren’s disease (SjD).

Methods

SGECs from SjD patients and controls were analysed for m6A writers METTL3 and METTL14 expression using RNA-seq, quantitative PCR and immunohistochemistry. Functional assays assessed the impact ofMETTL3knockdown or pharmacological inhibition on proinflammatory gene expression and immune cell interactions (using transwell and coculture systems). Mechanistic studies examined METTL3-mediated m6A modifications in double-stranded RNA (dsRNA) formation through immunofluorescence. Unsupervised clustering identified patterns of interferon activation in salivary glands and their correlation with m6A writers.

Results

METTL3 and METTL14 were elevated in SGEC from SjD patients in comparison to controls. Paradoxically, inhibiting METTL3 increased proinflammatory gene expression, enhancing SGEC’s ability to attract immune cells and activate B cells. Conversely, inhibiting the eraser FTO had the opposite effect. METTL3-mediated m6A modifications prevented dsRNA formation and IFN signalling activation. SGEC from SjD showed insufficientMETTL3upregulation compared with controls in response to inflammatory triggers, indicating a limited capacity to regulate the inflammatory response. SjD patients with elevated disease activity and higher interferon signature exhibit reducedMETTL3expression.

Conclusions

Impairment of m6A modifications in SGEC in response to inflammatory triggers favour the formation of dsRNA, potentially amplifying the interferon loop and contributing to SjD pathogenesis.

Members

STEPHAN VAGNER

Directeur de recherche Inserm