TL1A/DR3 signaling deletion attenuates mucosal inflammation and alveolar bone loss in murine periodontitis

Periodontitis is a chronic inflammatory disease leading to progressive alveolar bone loss and destruction of tooth-supporting tissues. While dental biofilm initiates the disease, the host's immune response drives much of the tissue damage. Current therapies often focus on biofilm control, but modulating the immune response remains a critical unmet need. The TL1A/DR3 (TNFSF15/TNFRSF25) axis is a known regulator of mucosal immune responses, yet its specific contribution to the immune amplification and tissue destruction in periodontal disease has been unclear.

Researchers investigated the role of TL1A/DR3 signaling in periodontitis using SAMP1/YitFc (SAMP) mice, a model that spontaneously develops ileitis and periodontal disease. They compared disease progression in wild-type SAMP mice, SAMPxDR3-/- mice (genetically deficient in DR3), and healthy AKR (parental) controls. Key assessments included periodontal architecture and alveolar bone loss. Gingival tissues were analyzed for gene expression (Tnfsf15, Tnfrsf25), inflammatory cytokine levels (IL-17, TNF-α, IL-1β), and immune cell populations (CD4+ T helper cells, neutrophils) to characterize the immune response.

Wild-type SAMP mice exhibited increased gingival expression of both Tnfsf15 (encoding TL1A) and Tnfrsf25 (encoding DR3), with expression levels positively correlating with disease severity. This was accompanied by elevated levels of IL-17, TNF-α, and IL-1β, and increased numbers of CD4+ T helper cells and neutrophils in the gingival tissues. These findings indicate a robust inflammatory response in diseased wild-type animals. Conversely, DR3 deficiency significantly mitigated these inflammatory markers.

SAMPxDR3-/- mice demonstrated markedly attenuated alveolar bone loss and improved periodontal architecture, restoring a phenotype comparable to healthy AKR controls.