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Autophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL\u20101\u03b2 overproduction, thereby suggesting autophagy regulation as a potential therapeutic modality. Trehalose is a disaccharide sugar with known pro\u2010autophagy activity and effective in alleviating diverse inflammatory diseases. We sought to investigate the therapeutic potential of autophagy\u2010enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism focusing on macrophage IL\u20101\u03b2 production in ECRS pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the therapeutic effects of trehalose and saccharin on macrophage IL\u20101\u03b2 production and eosinophilia in the mouse model of ECRS with myeloid cell\u2010specific autophagy\u2010related gene 7 (<jats:italic>Atg7<\/jats:italic>) deletion. The mechanisms underlying their anti\u2010inflammatory effects were assessed using specific inhibitor, genetic knockdown or knockout, and overexpression of cognate receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Unexpectedly, trehalose significantly attenuated eosinophilia and disease pathogenesis in ECRS mice caused by autophagy deficiency in myeloid cells. This autophagy\u2010independent effect was associated with reduced macrophage IL\u20101\u03b2 expression. Various sugars recapitulated the anti\u2010inflammatory 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\u20101\u03b2 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results revealed a previously unappreciated anti\u2010inflammatory effect of STR agonists, particularly trehalose and saccharin, and may provide an alternative strategy to autophagy modulation in the ECRS treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1021","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T18:38:46Z","timestamp":1661107126000},"source":"Crossref","is-referenced-by-count":13,"title":["Sweet taste receptor agonists attenuate macrophage IL\u20101\u03b2 expression and eosinophilic inflammation linked to autophagy deficiency in myeloid 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