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

Abstract

Background Eosinophilic inflammation is a hallmark of refractory chronic rhinosinusitis (CRS) and considered a major therapeutic target. Autophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL‐1β 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‐1β production in ECRS pathogenesis. Methods We investigated the therapeutic effects of trehalose and saccharin on macrophage IL‐1β 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‐1β 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‐1β 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.

Impaired autophagy in myeloid cells aggravates psoriasis-like skin inflammation through the IL-1β/CXCL2/neutrophil axis

“…Saccharin exerts an anti-inflammatory effect by inhibiting iNOS expression in the RAW 264.7 macrophage cell line [52] and reducing IL-1β mRNA expression in the 3T3-L1 adipocyte cell line [53]. Our previous study revealed that saccharin reduces IL-1β production from macrophages via a mechanism dependent on the sweet-taste receptor T1R3 but independent of autophagy and thereby attenuates eosinophilic inflammation in a murine model of ECRS [48]. In diverse inflammatory disorders including psoriasis, the role of autophagy depends on the cell type; therefore, targeting autophagy systemically as a therapeutic modality is challenging [54,55].…”

“…Our previous study revealed that artificial sugars, particularly saccharin, exert an anti-inflammatory effect on macrophage IL-1β production in an autophagy-independent manner [48]. Based on this finding, we investigated whether saccharin ameliorates IMQ-induced psoriatic skin inflammation in Atg7 fl/fl ;LysM-Cre mice.…”

Autophagy in chronic rhinosinusitis with or without nasal polyps

“…Moreover, the researchers demonstrated that blockade of the IL-1 receptor could alleviate eosinophilic inflammation, suggesting an IL-1 dependent pathway in eCRS due to autophagy deficiency. In a separate study, Lee et al (2022) discovered that the anti-inflammatory effects of sweet taste receptor (STR) agonists, particularly trehalose, significantly mitigated eosinophilia, and disease pathogenesis in eCRS mice with autophagy deficiency in myeloid cells. Their mechanistic investigation revealed the involvement of T1R3 in reducing macrophage IL-1β production and eosinophilia in CRS, which was supported by genetic manipulation of T1R3 expression in macrophages and treatment with the T1R3 antagonist gurmarin.…”

“…Future in vitro experiments using both cell types could shed light on the differences in autophagy levels and their impact on CRS progression. The review focused on eCRS models, leaving room for further exploration of autophagy differences in non-eCRS models ( Choi et al, 2018 ; Lee et al, 2022 ). Non-type 2 inflammation in CRS, represented by LPS, IFN-λ, and HNE-stimulated HNEpCs, often shows autophagy excess involving AMPK-mTOR, JNK–AP-1, and HNE-TRAF6 pathways ( Wang et al, 2017a ; Wang et al, 2017b ; Ye et al, 2019 ).…”

“…Their mechanistic investigation revealed the involvement of T1R3 in reducing macrophage IL-1β production and eosinophilia in CRS, which was supported by genetic manipulation of T1R3 expression in macrophages and treatment with the T1R3 antagonist gurmarin. This research highlighted a previously overlooked antiinflammatory target, offering a potential strategy for modulating autophagy in the treatment of eCRS (Lee et al, 2022). NFs isolated from CRSwNP patients were cultured to investigate the autophagy pathway.…”