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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Max Planck Society; Xi'an Jiaotong University; Max Planck Society; Goethe University Frankfurt; German Centre for Cardiovascular Research; Goethe University Frankfurt; University of Bonn; University of Bonn; Goethe University Frankfurt
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13210
• DOI: 10.1073/pnas.2407130121
• 发表日期: 2024-10-08
• 关键词: macrophage phagocytosis; lipid mediators; e-2 binding; RESOLUTION; activation; identification; disease; toxin; lipopolysaccharide; expression

摘要

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.