GLP-1 Receptor Signaling Differentially Modifies the Outcomes of Sterile vs Viral Pulmonary Inflammation in Male Mice
GLP-1 Receptor Signaling Differentially Modifies the Outcomes of Sterile vs Viral Pulmonary Inflammation in Male Mice
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DOI：
10.1210/endocr/bqaa201
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发表时间：
2020-12-01
期刊：
影响因子：
4.8
通讯作者：
Yamada, Yuichiro
中科院分区：
文献类型：
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作者：
Sato, Takehiro;Shimizu, Tatsunori;Yamada, Yuichiro
许多疾病状态，包括 2 型糖尿病 (T2D)，都与肺部感染风险增加相关。胰高血糖素样肽 1 (GLP-1) 受体激动剂用于治疗 T2D，并通过单一、明确的 GLP-1 受体 (GLP-1R) 发挥抗炎作用。尽管 GLP-1R 在肺部高度表达，但人们对 GLP-1R 在肺部炎症中的作用知之甚少。在这里，我们研究了感染性和非感染性肺部炎症中 GLP-1R 活性的增加或丧失的后果。我们在博来霉素诱导的非感染性肺损伤和流感病毒感染的情况下研究了用 GLP-1R 激动剂治疗的野生型小鼠和 Glp1r(-/-) 小鼠。 GLP-1R 的缺失减轻了博来霉素诱导的肺损伤的严重程度，而 GLP-1R 信号的激活则通过交感神经系统增加了肺部炎症。相比之下，GLP-1R激动剂降低了实验性流感病毒感染小鼠的病原体负荷，并与细胞内干扰素诱导型GTP酶表达增加相关。值得注意的是，GLP-1受体激动剂利拉鲁肽提高了流感病毒感染后的存活率。我们的结果揭示了 GLP-1 系统在肺损伤反应中的环境依赖性作用。值得注意的是，GLP-1R 激动剂在实验性流感病毒感染环境中的治疗反应可能与正在进行的针对易受病毒性肺损伤的 T2D 患者的 GLP-1R 激动剂研究相关。
A number of disease states, including type 2 diabetes (T2D), are associated with an increased risk of pulmonary infection. Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat T2D and exert anti-inflammatory actions through a single, well-defined GLP-1 receptor (GLP-1R). Although highly expressed in the lung, little is known about the role of the GLP-1R in the context of pulmonary inflammation. Here we examined the consequences of gain or loss of GLP-1R activity in infectious and noninfectious lung inflammation. We studied wild-type mice treated with a GLP-1R agonist, and Glp1r(-/-) mice, in the setting of bleomycin-induced noninfectious lung injury and influenza virus infection. Loss of the GLP-1R attenuated the severity of bleomycin-induced lung injury, whereas activation of GLP-1R signaling increased pulmonary inflammation via the sympathetic nervous system. In contrast, GLP-1R agonism reduced the pathogen load in mice with experimental influenza virus infection in association with increased expression of intracellular interferon-inducible GTPases. Notably, the GLP-1 receptor agonist liraglutide improved the survival rate after influenza virus infection. Our results reveal context-dependent roles for the GLP-1 system in the response to lung injury. Notably, the therapeutic response of GLP-1R agonism in the setting of experimental influenza virus infection may have relevance for ongoing studies of GLP-1R agonism in people withT2D susceptible to viral lung injury.