TL1A/DR3 signaling deletion attenuates mucosal inflammation and alveolar bone loss in a murine model of spontaneous periodontitis.

TL1A and its receptor DR3 are key regulators of mucosal immune responses, but their role in periodontal disease is unknown. Herein, we investigated whether TL1A/DR3 signaling contributes to mucosal immune amplification and tissue-destructive inflammation in periodontitis using SAMP1/YitFc (SAMP) mice, which develop spontaneous ileitis and periodontal disease. DR3 deficiency markedly attenuated alveolar bone loss and improved periodontal architecture, restoring a phenotype comparable to healthy AKR (parental) controls. Gingival tissues from wild-type SAMP mice exhibited increased expression of both Tnfsf15 (encoding TL1A) and Tnfrsf25 (encoding DR3), with both positively correlating with disease severity. This was accompanied by elevated levels of IL-17, TNF-α, and IL-1β, and by increased numbers of CD4+ T helper cells and neutrophils. Conversely, SAMPxDR3-/- mice exhibited reduced inflammatory cytokine production and immune cell accumulation. These findings support a model in which the TL1A/DR3 axis is associated with amplification of mucosal immune responses in periodontal disease, linking effector T cell activation, increased cytokine production, and recruitment of innate immune cells. Altogether, our data identify the TL1A/DR3 cytokine-receptor pair as a potential regulator of inflammatory circuits that drive periodontal pathology. Blocking this pathway may provide a therapeutic modality for patients affected by chronic periodontitis.