IL-17 Receptor inhibition with brodalumab limits experimental periodontitis

Periodontal disease (PD) is a chronic, biofilm-driven inflammatory condition in which connective tissue destruction and alveolar bone loss are driven largely by dysregulated host immunity. Prior experimental and clinical studies have linked IL-17 pathway activity to periodontal inflammation and treatment response, supporting its relevance as a therapeutic target in PD. Rather than targeting individual IL-17 isoforms, IL-17R blockade offers an alternative strategy because it serves as a shared downstream signaling node for multiple IL-17 family cytokines, potentially enabling broader modulation of inflammatory signaling. However, the therapeutic potential of IL-17R blockade in PD remains largely unexplored.

Gingival and salivary immune profiles and inflammatory markers were assessed in periodontally healthy, diseased, and post-therapy subjects. For mechanistic studies, mice subjected to ligature-induced periodontitis (LIP) received local gingival injection of the IL-17 receptor inhibitor brodalumab at 5 or 20 mg/kg, or vehicle control every 48 h. Animals were euthanized on day 4 or day 8 post-treatment, and gingival inflammatory responses were quantified by qPCR and flow cytometry. Alveolar bone outcomes were assessed by micro-CT, including CEJ-ABC distance as a measure of bone loss, and bone volume and bone mineral density as measures of bone quality.

Gingival and salivary CD4⁺IL-17⁺ T cells were increased in PD and were markedly reduced after therapy, supporting the association of IL-17-driven immune responses with disease activity and their resolution following treatment. This observation was validated in human gingival biopsies, where IL-17 expression was elevated in PD and markedly reduced after nonsurgical periodontal therapy, accompanied by lower inflammatory cytokine expression and a shift toward a healthy control profile. In LIP mice, local injection of brodalumab reduced gingival inflammatory transcripts, with IL-17A suppressed by day 4 and sustained through day 8, alongside reduced IL-17B, indicating broader dampening of IL-17 signaling. These changes were associated with reduced gingival neutrophil infiltration and M2-like macrophage skewing, indicating that brodalumab promotes the resolution of inflammation. Micro-CT demonstrated lower alveolar bone loss in a dose-dependent manner in brodalumab treated animals. Brodalumab also preserved bone quality, increasing bone volume and bone mineral density, most prominently at the higher dose, which approached no-ligature values by day 8.

Local gingival administration of brodalumab attenuates IL-17-associated inflammatory responses and protects against alveolar bone loss in experimental periodontitis. Our findings support IL-17R blockade as a promising host-modulatory strategy that could serve as an adjunct to conventional periodontal care to limit periodontal tissue destruction.