Keratan Sulfate Promotes Periodontitis Progression Via Tlr4/Nf-Κb Pathway

To explore the metabolic level and regulatory mechanism of keratan sulfate (KS) in periodontitis progression. KS secretion levels and FUT8 and CHST2 expression, alongside neutrophil and plasma cell infiltration, were analyzed in clinical gingival crevicular fluid (Health: n = 7; Periodontitis: n = 7) and gingival tissue samples (Health: n = 6; Periodontitis: n = 6) from patients using enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, western blot and multiplex immunohistochemistry. Patient samples were obtained with the approval of the Ethics Committee. In vitro cell experiments were conducted to verify KS expression and its regulatory mechanism in periodontitis progression. Comparisons between two groups were performed using an unpaired Student’s t-test or the Wilcoxon rank-sum test, with or without Benjamini-Hochberg adjustment. For multiple group comparisons, one-way ANOVA followed by Tukey’s multiple comparison test was applied. Statistical significance was set at P < 0.05. KS, FUT8, CHST2, plasma cells, and neutrophils were significantly elevated in clinical periodontitis samples. LPS upregulated FUT8 and CHST2, enhancing KS biosynthesis in human umbilical vein endothelial cells and gingival fibroblasts (HGFs), while KS promoted plasma cell and neutrophil recruitment by increasing CXCL2 and CXCL13 expression via the TLR4/NF-κB pathway in HGFs. Mechanistically, KS amplified LPS-induced TLR4/NF-κB activation, further stimulating KS biosynthesis and establishing a positive feedback loop. Our findings reveal a role of KS metabolism in shaping periodontal inflammatory microenvironment, suggesting that targeting KS metabolism may represent a potential therapeutic strategy for managing chronic inflammation in periodontitis.