XBP1 Knockdown Alleviates Pyroptosis and Promotes Th17/Treg Imbalance in Periodontitis by Inhibiting the IL-17 Signaling Pathway

Periodontitis is a long-lasting inflammatory condition that significantly affects people's quality of life. This research focused on examining the function and underlying mechanisms of X-box binding protein 1 (XBP1) in the pathogenesis of periodontitis. In vitro and in vivo models of periodontitis were established using lipopolysaccharide (LPS). The viability and apoptosis of periodontal ligament stem cells (PDLSCs) were assessed using the Cell Counting Kit-8 and flow cytometry assays, respectively. Reverse transcription-quantitative PCR, western blot, and enzyme-linked immunosorbent assays were employed to measure the levels of inflammatory factors and mediators associated with T helper 17 (Th17)/regulatory T cell (Treg) balance, pyroptosis, and the interleukin-17 (IL-17) pathway. Histological and immunohistochemical analyses were conducted to evaluate tissue damage and bone resorption markers. The IL-17 pathway was activated with SR0987 to explore the interactions between XBP1 and IL-17 signaling. XBP1 knockdown reduced apoptosis, pyroptosis, and inflammation, as indicated by lower levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-18) and pyroptosis-related proteins (ASC, GSDMD-N, NLRP3). XBP1 knockdown alleviated tissue damage, inflammatory cell infiltration, and bone destruction in rat models of periodontitis. XBP1 knockdown notably restored the Th17/Treg imbalance by suppressing Th17 differentiation and promoting Treg differentiation. Mechanistically, XBP1 knockdown inhibited the IL-17 signaling pathway, and IL-17Activator SR0987 significantly reversed the beneficial effects of XBP1 knockdown on periodontitis. XBP1 knockdown alleviated periodontitis by inhibiting the IL-17 signaling pathway, implying that XBP1 could serve as a promising therapeutic target for managing periodontal conditions.