Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.

中文翻译：

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中枢胰高血糖素样肽 1 受体激活抑制 Toll 样受体激动剂诱导的炎症

胰高血糖素样肽 1 受体激动剂 (GLP-1RA) 发挥与 2 型糖尿病慢性并发症相关的抗炎作用。尽管 GLP-1RA 直接通过肠道上皮内淋巴细胞 GLP-1R 减弱 T 细胞介导的肠道和全身炎症，但在 GLP-1R 广泛免疫表达缺失的情况下，GLP-1RA 如何抑制全身炎症仍不确定。在这里，我们发现 GLP-1R 激活减弱了多种 Toll 样受体激动剂对血浆肿瘤坏死因子 α (TNF-α) 的诱导。这些作用不是由造血或内皮 GLP-1R 介导的，而是需要中枢神经元 GLP-1R。在多种微生物脓毒症的盲肠浆模型中，GLP-1RA 同样需要神经元 GLP-1R 来减弱与脓毒症相关的有害反应，包括疾病、体温过低、全身炎症和肺损伤。从机制上讲，GLP-1R 激活通过 α-肾上腺素能、δ-阿片类药物和 κ-阿片类药物受体信号传导导致 TNF-α 减少。这些数据扩展了脑免疫网络的新兴概念，并提出了一种新的肠脑 GLP-1R 轴来抑制外周炎症。