Significance Specialized pro-resolving mediators (SPMs) are poly-unsaturated fatty acid derivatives, which have anti-inflammatory and pro-resolving properties. However, their mechanism of action is still unclear. Here, we report that major synthetic… Click to show full abstract
Significance Specialized pro-resolving mediators (SPMs) are poly-unsaturated fatty acid derivatives, which have anti-inflammatory and pro-resolving properties. However, their mechanism of action is still unclear. Here, we report that major synthetic SPMs function as positive allosteric modulators (PAM) of prostaglandin E2 receptor subtype 4 (EP4). Interestingly, this modulation of EP4 in macrophages not only enhances coupling of EP4 to the Gs signaling pathway but additionally endows EP4 with the new ability to couple to Gi-proteins, thereby enhancing the phagocytic activity of macrophages. Our findings identify a central mechanism of action for SPMs and may enable the development of synthetic PAMs of the EP4 receptor as a therapeutic strategy for inflammatory diseases.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2024
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