Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers.

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.