Glucagon-like peptide-1 cleavage product GLP-1(9-36) reduces neuroinflammation from stroke via the activation of insulin-like growth factor 1 receptor in astrocytes
Glucagon-like peptide-1 cleavage product GLP-1(9-36) reduces neuroinflammation from stroke via the activation of insulin-like growth factor 1 receptor in astrocytes
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DOI：
10.1016/j.ejphar.2020.173581
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发表时间：
2020-11-15
影响因子：
5
通讯作者：
Zhang, Huinan
中科院分区：
文献类型：
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作者：
Huang, Jing;Liu, Yunhan;Zhang, Huinan
胰高血糖素样肽-1（GLP-1）是一种内源性肠道激素，是通过刺激胰岛素分泌维持葡萄糖稳态的关键调节因子。其天然裂解产物GLP-1（9-36），主要由于其对GLP-1受体的低亲和力而被认为是一种“生物非活性”代谢物，具有独特的性质，如心血管保护。GLP-1（9-36）在脑缺血再灌注损伤中的作用及机制尚不清楚。在这里，我们报告了GLP-1（9-36）在成年小鼠中的全身应用促进了大脑中动脉闭塞和再灌注后的功能恢复，并减少了梗死体积、星形胶质细胞增生和神经元凋亡。有趣的是，在GLP-1受体敲除（Glp-1 r（KO））小鼠中仍观察到这些效应，但在胰岛素样生长因子1（IGF-1）受体敲除（Igf-1 r（KD））小鼠中部分逆转。培养原代星形胶质细胞并进行氧-葡萄糖剥夺/复氧（OGD/R），酶联免疫吸附试验表明GLP-1（9-36）预处理降低了肿瘤坏死因子-α、白细胞介素（IL）-1 β和IL-6水平。这种作用在Glp-1 r（KO）星形胶质细胞中未减弱，但在Igf-1 r（KO）星形胶质细胞中逆转，强调GLP-1（9-36）在星形胶质细胞中的抗炎作用不依赖于GLP-1受体信号传导，而是由IGF-1受体介导。免疫沉淀实验表明，GLP-1（9-36）直接与星形胶质细胞中的IGF-1受体相互作用。Western blot数据表明，GLP-1（9-36）在OGD/R损伤后激活星形胶质细胞中的IGF-1受体和下游PI 3 K-AKT通路，其通过与IGF-1受体自磷酸化抑制剂苦鬼臼脂预孵育而被消除。因此，我们的研究结果表明，GLP-1（9-36）通过与IGF-1受体相互作用减少星形胶质细胞中的炎症，从而改善卒中结局。
Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a "bio-inactive" metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Little is known about the effects and mechanisms of GLP-1 (9-36) in cerebral ischemia and reperfusion injury. Here, we report that systemic application of GLP-1 (9-36) in adult mice facilitated functional recovery and reduced infarct volume, astrogliosis, and neuronal apoptosis following middle cerebral artery occlusion and reperfusion. Interestingly, these effects were still observed in GLP-1 receptor knockout (Glp-1r(KO)) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1r(KD)) mice. Primary astrocytes were cultured and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and enzyme-linked immunosorbent assay indicated that GLP-1 (9-36) pretreatment reduces tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6 levels. This effect was not diminished in Glp-1r(KO) astrocytes but was reversed in Igf-1r(KO) astrocytes, emphasizing that the anti-inflammatory effect of GLP-1 (9-36) in astrocytes is independent of GLP-1 receptor signaling and is instead mediated by IGF-1 receptor. Immunoprecipitation experiments showed that GLP-1 (9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-1 (9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD/R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. Thus, our findings suggest that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor.