Abstract
Inflammation is a protective response to pathogens and injury. To be effective it needs to be resolved by endogenous mechanisms in order to avoid prolonged and excessive inflammation, which can become chronic. Specialized pro-resolving mediators (SPMs) are a group of lipids derived from omega-3 fatty acids, which can induce the resolution of inflammation. How SPMs exert their anti-inflammatory and pro-resolving effects is, however, not clear. Here, we show that SPMs such as protectins, maresins, and D-series resolvins function as biased positive allosteric modulators (PAM) of the prostaglandin E2 (PGE2) receptor EP4 through an intracellular binding site. They increase PGE2-induced Gs-mediated formation of cAMP and thereby promote anti-inflammatory signaling of EP4. In addition, SPMs endow the endogenous EP4 receptor on macrophages with the ability to couple to Gi-type G-proteins, which converts the EP4 receptor on macrophages from an anti-phagocytotic receptor to one increasing phagocytosis, a central mechanism of the pro-resolving activity of synthetic SPMs. In the absence of the EP4 receptor, SPMs lose their anti-inflammatory and pro-resolving activity in vitro and in vivo. Our findings reveal an unusual mechanism of allosteric receptor modulation by lipids and provide a mechanism by which synthetic SPMs exert pro-resolving and anti-inflammatory effects, which may facilitate approaches to treat inflammation.