WTAP Promotes Macrophage Pyroptosis and Exacerbates Periodontal Inflammation in Periodontitis Via the circPVT1/KLF6/SPRY1 Axis

Periodontitis (PD) is a chronic inflammatory periodontal disease, with macrophage pyroptosis as a key participator. This research analyzed the mechanism of WTAP in PD via macrophage pyroptosis. Periodontal tissues were collected from PD patients and healthy volunteers. Mouse and cell models of PD were established. WTAP, circPVT1, KLF6, and SPRY1 were examined by RT-qPCR or Western blot. IL-6, TNF-α, IL-1β, and IL-18 were quantified by ELISA. Pyroptosis-related factors were analyzed by Western blot. Caspase-1 activity and LDH content were determined using kits. Cell viability and pyroptosis were detected. The enrichment of m6A and IGF2BP2 on circPVT1 was evaluated by RIP and MeRIP. The subcellular localization of circPVT1 was determined. The binding of KDM4C and HuR to circPVT1 was verified. KDM4C and H3K9me3 enrichments on the KLF6 promoter were examined. Colocalization of circPVT1, KDM4C, and HuR was detected. The binding of HuR to SPRY1 was verified. SPRY1 stability was assessed. WTAP, circPVT1, KLF6, and SPRY1 were upregulated in PD. WTAP downregulation alleviated pyroptosis in the PD models. WTAP increased circPVT1 expression by enhancing m6A modification via IGF2BP2. Nuclear circPVT1 upregulated KLF6 expression by reducing H3K9me3 modification on the KLF6 promoter through KDM4C, while cytoplasmic circPVT1 bound to HuR to elevate SPRY1 expression. Overexpression of circPVT1, KLF6 or SPRY1 partially reversed the inhibitory effect of WTAP knockdown on LPS-induced pyroptosis in cells. WTAP increases circPVT1 expression by promoting m6A modification via IGF2BP2. CircPVT1 potentially promotes macrophage pyroptosis and accelerates periodontal inflammation via KLF6 and SPRY1.