ELAVL1 modulates periodontal ligament fibroblast pyroptosis in periodontitis through the JAK2/STAT3/NLRP3 axis

Abstract Periodontitis is an inflammatory disorder that leads to the destruction of periodontal tissues. Pyroptosis, related to the NLRP3 inflammasome, is implicated in the pathogenesis of periodontitis. ELAVL1, an m6A reader, is associated with inflammatory responses; however, its role in periodontitis requires further clarification. Our research elucidated the regulatory functions of ELAVL1 in periodontitis and explored the underlying mechanisms. Expression of ELAVL1 in periodontitis mice and P.g-LPS-induced PLFs was assessed via qRT-PCR and western blot. ELISA was performed to analyze IL-1β and IL-18 levels. The associated protein levels of the NLRP3 inflammasome, bone formation, and JAK2/STAT3 pathway were detected using western blot. Pyroptosis was evaluated by flow cytometry. RIP, MeRIP, and dual-luciferase reporter assay were performed to validate the association between ELAVL1 and JAK2 mRNA. Immunofluorescence was used to detect ELAVL1, NLRP3 and Vimentin expression in periodontal tissues. The pathological changes in periodontal tissues were determined by micro-CT and H&E staining. We found that ELAVL1 was upregulated in periodontitis tissues and P.g-LPS-stimulated PLFs. Mechanistically, ELAVL1 bound to JAK2 mRNA, enhancing its m6A modification and stability, thereby activating the JAK2/STAT3 signaling. Knockdown of ELAVL1 decreased NLRP3 inflammasome activation and pyroptosis in PLFs, inhibited inflammatory factor secretion, and inhibited activation of the JAK2/STAT3 pathway. However, these effects were partially reversed following treatment with C-A1. Furthermore, ELAVL1 knockdown attenuated alveolar bone loss, decreased p-JAK2 and p-STAT3 levels, and suppressed NLRP3-mediated pyroptosis in vivo. We conclude that ELAVL1 promotes periodontitis by mediating m6A modification of JAK2 and activating the JAK2/STAT3/NLRP3-mediated pyroptosis, suggesting its promise as a novel treatment target for periodontitis.