Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers
Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers
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经典的 Gs-cAMP/PKA/CREB 和替代的 Gs-cAMP/PKA/p38 beta/CREB 信号通路介导艾塞那肽刺激的 M2 小胶质细胞标记物的表达
DOI：
10.1016/j.jneuroim.2017.12.005
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发表时间：
2018-03-15
影响因子：
3.3
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Wu, Hai-Yun;Tang, Xue-Qi;Wang, Yong-Xiang
GLP-1受体激动剂艾塞那肽和GLP-1可促进单核细胞/巨噬细胞和小胶质细胞的M2型极化。本研究探讨了艾塞那肽刺激M2小胶质细胞特异性基因表达的信号基础，包括细胞质标记物Arg 1、表面标记物CD 206和分泌蛋白标记物IL-4。在培养的原代小胶质细胞中用exenlavin处理浓度依赖性地刺激Arg 1、CD 206和IL-4的表达，但没有显著改变LPS刺激的TNF-α、IL-1 β和IL-6的表达。GLP-1受体拮抗剂exendin（9-39）完全阻止了exenvatinib的刺激作用，但LPS的应用并未改变该作用。此外，腺苷酸环化酶抑制剂DDA，PKA抑制剂H89和CREB抑制剂KG 501完全阻断艾塞那肽诱导的Arg 1，CD 206和IL-4的过表达。此外，艾塞那肽刺激的Arg 1和CD 206的表达被p38 MAPK抑制剂SB 203580和基因沉默物siRNA/p38 β完全阻断（但不是siRNA/p38 α），而表达的IL-4不被p38抑制剂或其他MAPK亚型抑制剂显著改变。这些发现表明，经典的Gs-cAMP/PKA/CREB和替代的Gs-cAMP/PKA/p38 β/CREB均介导GLP-1受体激动诱导的M2小胶质细胞生物标志物的过表达。
GLP-1 receptor agonists, exenatide and GLP-1, promoted M2 type polarization in monocytes/macrophages and microglial cells. This study explored the signal basis underlying exenatide-stimulated expression of M2 microglia-specific genes, including the cytoplasmic marker Arg 1, surface marker CD206, and secretion protein marker IL-4. Treatment with exenatide in cultured primary microglial cells concentration dependently stimulated the expression of Arg 1, CD206 and IL-4, but did not significantly alter LPS-stimulated expression of TNF-alpha, IL-1 beta and IL-6. The stimulatory effects of exenatide were completely prevented by the GLP-1 receptor antagonist exendin(9-39), but not altered by application of LPS. Furthermore, the adenylyl cyclase inhibitor DDA, PKA inhibitor H89 and CREB inhibitor KG501 completely blocked exenatide-induced overexpression of Arg 1, CD206 and IL-4. In addition, exenatide-stimulated expression of Arg 1 and CD206 was totally blocked by the p38 MAPK inhibitor SB203580 and gene silencer siRNA/p38 beta (but not siRNA/p38 alpha), whereas the expressed IL-4 was not significantly altered by the p38 inhibitor or other MAPK subtype inhibitors. These findings revealed that both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38 beta/CREB mediated GLP-1 receptor agonism-induced overexpression of M2 microglial biomarkers.