Targeting the IL-6–Th17–Neutrophil Axis Reduces Local Inflammation in Stomatitis

Abstract

Recurrent aphthous stomatitis (RAS) is a common chronic oral disease with unclear pathogenesis. Chronic inflammation associated with RAS has been linked to the dysregulation of local immune responses. We used a murine model of acetic acid–induced chemical stomatitis (CS) to assess changes in the systemic and local immune environments of CS mice relative to healthy mice. Flow cytometry revealed a significant increase in neutrophil infiltration and elevated proportions of Th1 (CD4⁺IFN-γ⁺) and Th17 (CD4⁺IL-17a⁺) cells in the lingual mucosa of CS mice 7 d after CS induction, indicating an active inflammatory response in the CS immune microenvironment. Given that Th17 cells indirectly recruit neutrophils, we used Rorc^-/- mice to evaluate the effects of Th17 cell depletion. Neutrophil infiltration was markedly reduced, and decreased tissue damage was observed in the lingual mucosa of Rorc^-/- mice, as confirmed by hematoxylin and eosin staining. To further investigate the mechanism underlying Th17 cell generation in stomatitis, we induced CS in Il6ra^-/- mice, which exhibited significantly reduced inflammatory cell infiltration and ulcer severity in the lingual mucosa. Treatment with an anti-Ly6G antibody treatment, which can directly target and deplete neutrophils, also significantly reduced local inflammation in the CS mouse immune microenvironment and diminished Th1 and Th17 cell infiltration, indicating a positive feedback loop between Th17 cells and neutrophils in stomatitis. In conclusion, the IL-6–Th17–neutrophil axis plays a critical role in stomatitis pathogenesis, suggesting that targeting this axis could present a novel immunotherapeutic strategy for alleviating mucosal damage in patients with RAS.