Sweet taste receptor agonists attenuate macrophage IL-1β expression and eosinophilic inflammation linked to autophagy deficiency in myeloid cells

Background: Eosinophilic inflammation is a hallmark of refractory chronic rhinosinusitis (CRS) and considered a major therapeutic target. Au tophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL-1 beta overproduction, thereby suggesting autophagy regulation as a potential therapeutic modality. Trehalose is a disaccharide sugar with known pro-autophagy activity and effective in alleviating diverse inflammatory diseases. We sought to investigate the therapeutic potential of autophagy-enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism focusing on macrophage IL-1 beta production in ECRS pathogenesis. Methods: We investigated the therapeutic effects of trehalose and saccharin on macrophage IL-1 beta production and eosinophilia in the mouse model of ECRS with myeloid cell-specific autophagy-related gene 7 (Atg7) deletion. The mechanisms underlying their anti-inflammatory effects were assessed using specific inhibitor, genetic knockdown or knockout, and overexpression of cognate receptors. Results: Unexpectedly, trehalose significantly attenuated eosinophilia and disease pathogenesis in ECRS mice caused by autophagy deficiency in myeloid cells. This autophagy-independent effect was associated with reduced macrophage IL-1 beta expression. Various sugars recapitulated the anti-inflammatory effect of trehalose, and saccharin was particularly effective amongst other sugars. The mechanistic study revealed an involvement of sweet taste receptor (STR), especially T1R3, in alleviating macrophage IL-1 beta production and eosinophilia in CRS, which was supported by genetic depletion of T1R3 or overexpression of T1R2/T1R3 in macrophages and treatment with the T1R3 antagonist gurmarin. Conclusion: Our results revealed a previously unappreciated anti-inflammatory effect of STR agonists, particularly trehalose and saccharin, and may provide an alternative strategy to autophagy modulation in the ECRS treatment.

Automated summary

This study found that sweet taste receptor agonists such as trehalose and saccharin have anti-inflammatory effects and can alleviate the occurrence of refractory chronic rhinosinusitis. Trehalose can reduce the production of IL-1 beta in macrophages, thereby alleviating the inflammatory pathogenesis.