Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Department of Clinical Laboratory Science, Catholic University of Pusan, Busan, Korea.
Clin Transl Med. 2022 Aug;12(8):e1021. doi: 10.1002/ctm2.1021.
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.
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.
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.
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.
嗜酸性粒细胞炎症是难治性慢性鼻-鼻窦炎（CRS）的标志，被认为是主要的治疗靶点。髓系细胞中的自噬缺陷通过巨噬细胞 IL-1β的过度产生在嗜酸性 CRS（ECRS）中起因果作用，从而表明自噬调节作为一种潜在的治疗方式。海藻糖是一种具有已知自噬促进活性的二糖，可有效缓解多种炎症性疾病。我们试图研究自噬增强剂海藻糖或相关糖化合物的治疗潜力，以及在 ECRS 发病机制中聚焦于巨噬细胞 IL-1β产生的潜在机制。
我们研究了自噬相关基因 7（Atg7）在髓系细胞中特异性缺失的 ECRS 小鼠模型中，海藻糖和糖精对巨噬细胞 IL-1β产生和嗜酸性粒细胞增多的治疗作用。使用特异性抑制剂、基因敲低或敲除以及同源受体的过表达评估其抗炎作用的机制。
出乎意料的是，海藻糖显著减轻了由髓系细胞自噬缺陷引起的 ECRS 小鼠的嗜酸性粒细胞增多和疾病发病机制。这种与自噬无关的作用与巨噬细胞 IL-1β表达的减少有关。各种糖重现了海藻糖的抗炎作用，而糖精在其他糖中效果尤为显著。机制研究表明，甜味受体（STR），特别是 T1R3，参与了减轻 CRS 中的巨噬细胞 IL-1β产生和嗜酸性粒细胞增多，这得到了 T1R3 在巨噬细胞中的基因缺失或过表达以及 T1R3 拮抗剂格尔马林治疗的支持。
我们的结果揭示了 STR 激动剂，特别是海藻糖和糖精的先前未被认识到的抗炎作用，并且可能为 ECRS 治疗中的自噬调节提供了替代策略。
