Succinate–succinate receptor 1 axis amplifies eosinophilic inflammation in nasal mucosa

Background: Emerging evidence indicates that the succinate–succinate receptor 1 (SUCNR1) axis promotes metabolic reprogramming and plays a pivotal role in shaping immune responses, yet the contribution of the succinate–SUCNR1 axis to eosinophilic inflammation of the nasal mucosa remains poorly understood. Objective: This study aimed to investigate the role of the succinate–SUCNR1 axis in eosinophilic inflammation of the nasal mucosa. Methods: SUCNR1 expression and cellular localization were evaluated using immunohistochemistry, immunofluorescence, and single-cell RNA sequencing in human nasal tissues. The functional role of the succinate–SUCNR1 axis was assessed in a papain-induced murine eosinophilic rhinosinusitis model using succinate administration with or without the SUCNR1 antagonist compound 7a. In addition, succinate was administered to healthy mice to evaluate its effects on normal nasal mucosa. Results: SUCNR1 + cells were significantly upregulated in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) compared with noneosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP; fold change = 6.33, P < 0.0001) and controls (fold change = 16.89, P < 0.0001). SUCNR1 was predominantly expressed in M2 macrophages, and CD163 + SUCNR1 + M2 macrophage counts were strongly correlated with tissue eosinophil counts ( r = 0.8092, P < 0.0001). In murine eosinophilic rhinosinusitis, lamina propria SUCNR1 + cells (fold change = 6.71, P < 0.001) and serum succinate (fold change = 1.78, P < 0.01) were elevated. Succinate administration exacerbated eosinophil infiltration in nasal mucosa (fold change = 2.0, P < 0.001) and peripheral blood eosinophilia (fold change = 1.83, P < 0.01), effects that were reversed by SUCNR1 antagonist compound 7a (both P < 0.01). Meanwhile, exogenous succinate did not induce significant nasal inflammation or blood eosinophilia in healthy mice versus vehicle controls ( P > 0.05). Conclusion: SUCNR1 was significantly upregulated in nasal polyps from patients with ECRSwNP and was predominantly expressed in M2 macrophages. The succinate–SUCNR1 axis is an eosinophilic inflammatory amplification pathway in nasal mucosa.