SPMs exert anti- inflammatory and pro- resolving effects through positive 
allosteric modulation of the prostaglandin EP4 receptor

Alnouri, Mohamad Wessam; Roquid, Kenneth Anthony; Bonnavion, Remy; Cho, Haaglim; Heering, Jan; Kwon, Jeonghyeon; Jaeger, Yannick; Wang, ShengPeng; Guenther, Stefan; Wettschureck, Nina; Geisslingerb, Gerd; Gurke, Robert; Mueller, Christa E.; Proschak, Ewgenij; Offermanns, Stefan

doi:10.1073/pnas.2407130121

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SPMs exert anti- inflammatory and pro- resolving effects through positive allosteric modulation of the prostaglandin EP4 receptor

MPS-Authors

/persons/resource/persons261924

Alnouri, Mohamad Wessam
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248835

Roquid, Kenneth Anthony
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons239389

Bonnavion, Remy
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons261926

Cho, Haaglim
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons269940

Kwon, Jeonghyeon
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251580

Jaeger, Yannick
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224209

Wang, ShengPeng
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224211

Wettschureck, Nina
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224185

Offermanns, Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Alnouri, M. W., Roquid, K. A., Bonnavion, R., Cho, H., Heering, J., Kwon, J., et al. (2024). SPMs exert anti- inflammatory and pro- resolving effects through positive allosteric modulation of the prostaglandin EP4 receptor. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 121(41): e2407130121. doi:10.1073/pnas.2407130121.

Cite as: https://hdl.handle.net/21.11116/0000-0010-3AD4-E

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 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 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 and anti- inflammatory effects, which may facilitate approaches to treat inflammation.