BackgroundAnti‐inflammatory effects of incretin signaling through the glucagon‐like peptide‐1 receptor (GLP‐1R) and the glucose‐dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP‐1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP‐1R and GIPR signaling together additively inhibits allergen‐induced lung and airway inflammation.MethodsWT (C57BL/6J), GLP‐1R knockout (KO), GIPR KO, and GLP‐1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt‐Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen‐induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2).ResultsAlt‐Ext‐induced IL‐33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP‐1R/GIPR DKO mice challenged with Alt‐Ext compared to the other strains. Furthermore, Alt‐Ext‐induced protein expression of IL‐5, IL‐13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP‐1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM‐1 expression on lung epithelial cells was increased in GLP‐1R/GIPR DKO mice challenged with Alt‐Ext compared to the other 3 strains.ConclusionsDeficiency of both GLP‐1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP‐1R and GIPR signaling should be explored for the treatment of asthma.

中文翻译：

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内源性胰高血糖素样肽 1 受体和葡萄糖依赖性促胰岛素多肽受体信号传导抑制气源性过敏原诱导的先天性气道炎症


背景 在小鼠中，通过胰高血糖素样肽-1 受体 （GLP-1R） 和葡萄糖依赖性促胰岛素多肽受体 （GIPR） 的肠促胰岛素信号转导具有抗炎作用。因此，我们假设通过内源性 GLP-1R 和 GIPR 的信号传导可单独减少过敏性气道炎症，并且 GLP-1R 和 GIPR 信号传导的组合共同抑制过敏原诱导的肺和气道炎症。方法用链格孢菌提取物 （Alt-Ext） 或载体鼻内攻击 WT （C57BL/6J）、GLP-1R 敲除 （KO）、GIPR KO 和 GLP-1R/GIPR 双 KO （DKO） 小鼠，以评估通过这些受体的信号传导对先天性过敏原诱导的炎症反应的影响，该反应主要由第 2 组先天淋巴细胞 （ILC2） 驱动。结果Alt-Ext 诱导的支气管肺泡灌洗液 （BALF） 中 IL-33 释放在小鼠菌株之间没有差异，但与其他菌株相比，用 Alt-Ext 攻击的 GLP-1R/GIPR DKO 小鼠胸腺基质淋巴细胞生成素 （TSLP） 显著增加。此外，Alt-Ext 诱导的肺匀浆中 IL-5 、 IL-13 、 CCL11 和 CCL24 的蛋白表达，BALF 中嗜酸性粒细胞、淋巴细胞和中性粒细胞的数量，以及肺 GATA3 + ILC2 的数量与其他 3 种菌株相比显著增加。此外，与其他 3 种菌株相比，用 Alt-Ext 攻击的 GLP-1R/GIPR DKO 小鼠肺上皮细胞上的 ICAM-1 表达增加。结论GLP-1R 和 GIPR 信号转导的缺陷共同增加了 TSLP 释放、ILC2 激活和对气源过敏原暴露的早期 2 型先天免疫反应。应探索 GLP-1R 和 GIPR 信号联合治疗哮喘。