CREB pathway links PGE2 signaling with macrophage polarization

Significance The second messenger cAMP exerts potent immunosuppressive effects on the innate immune system, in part by activating class IIa histone deacetylases, and thereby inhibiting NF-κB–dependent transcription. We found that cAMP also promotes M2 macrophage polarization by stimulating the cyclic AMP-responsive element binding (CREB)/cAMP-regulated transcriptional coactivators TORC1 pathway. In the setting of acute overnutrition, macrophage CREB inhibits the production of inflammatory mediators and contributes to the maintenance of insulin sensitivity.