King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
J Neuroimmunol. 2018 Mar 15;316:17-22. doi: 10.1016/j.jneuroim.2017.12.005. Epub 2017 Dec 12.
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-α, IL-1β 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/p38β (but not siRNA/p38α), 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/p38β/CREB mediated GLP-1 receptor agonism-induced overexpression of M2 microglial biomarkers.
GLP-1 受体激动剂艾塞那肽和 GLP-1 促进单核细胞/巨噬细胞和小胶质细胞向 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 Arg1、表面标记 CD206 和分泌蛋白标记 IL-4。艾塞那肽在培养的原代小胶质细胞中的处理浓度依赖性地刺激 Arg1、CD206 和 IL-4 的表达，但对 LPS 刺激的 TNF-α、IL-1β 和 IL-6 的表达没有显著影响。GLP-1 受体拮抗剂 exendin(9-39)完全阻断了艾塞那肽的刺激作用，但 LPS 的应用并未改变其作用。此外，腺苷酸环化酶抑制剂 DDA、PKA 抑制剂 H89 和 CREB 抑制剂 KG501 完全阻断了艾塞那肽诱导的 Arg1、CD206 和 IL-4 的过度表达。此外，艾塞那肽刺激的 Arg1 和 CD206 表达完全被 p38 MAPK 抑制剂 SB203580 和基因沉默 siRNA/p38β（而非 siRNA/p38α）阻断，而表达的 IL-4 不受 p38 抑制剂或其他 MAPK 亚型抑制剂的显著影响。这些发现表明，经典的 Gs-cAMP/PKA/CREB 和替代的 Gs-cAMP/PKA/p38β/CREB 都介导了 GLP-1 受体激动剂诱导的 M2 小胶质细胞生物标志物的过度表达。
