Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation

Lin Li; Nan Xu; Yulin He; Mingsui Tang; Binrui Yang; Jun Du; Liang Chen; Xiaowen Mao; Bing Song; Zhou Hua; Benqin Tang; Simon Ming-Yuen Lee

doi:10.1016/j.neurot.2024.e00479

Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation

Neurotherapeutics. 2024 Nov 27:e00479. doi: 10.1016/j.neurot.2024.e00479. Online ahead of print.

Authors

Lin Li¹, Nan Xu¹, Yulin He², Mingsui Tang³, Binrui Yang⁴, Jun Du⁴, Liang Chen⁴, Xiaowen Mao¹, Bing Song⁵, Zhou Hua⁶, Benqin Tang⁷, Simon Ming-Yuen Lee⁸

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
² State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
³ State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China; Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁴ Nutrilite Health Institute, Amway (Shanghai) Innovation & Science Co, Ltd, Shanghai, China.
⁵ Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁶ Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao ln-Depth Cooperation Zone in Hengqin, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou, China.
⁷ Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. Electronic address: tangbenqincy@gmail.com.
⁸ State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; Research Institute for Smart Ageing, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; PolyU-BGI Joint Research Centre for Genomics and Synthetic Biology in Global Ocean Resource, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. Electronic address: simon-my.lee@polyu.edu.hk.

PMID: 39609160
DOI: 10.1016/j.neurot.2024.e00479

Abstract

Microglia play a dual role in neuroinflammatory disorders that affect millions of people worldwide. These specialized cells are responsible for the critical clearance of debris and toxic proteins through endocytosis. However, activated microglia can secrete pro-inflammatory mediators, potentially exacerbating neuroinflammation and harming adjacent neurons. TREM2, a cell surface receptor expressed by microglia, is implicated in the modulation of neuroinflammatory responses. In this study, we investigated if and how Dehydroervatamine (DHE), a natural alkaloid, reduced the inflammatory phenotype of microglia and suppressed neuroinflammation. Our findings revealed that DHE was directly bound to and activated TREM2. Moreover, DHE effectively suppressed the production of pro-inflammatory cytokines, restored mitochondrial function, and inhibited NLRP3 inflammasome activation via activating the TREM2/DAP12 signaling pathway in LPS-stimulated BV2 microglial cells. Notably, silencing TREM2 abolished the suppression effect of DHE on the neuroinflammatory response, mitochondrial dysfunction, and NF-κB/NLRP3 pathways in vitro. Additionally, DHE pretreatment exhibited remarkable neuroprotective effects, as evidenced by increased neuronal viability and reduced apoptotic cell numbers in SH-SY5Y neuroblastoma cells co-cultured with LPS-stimulated BV2 microglia. Furthermore, in our zebrafish model, DHE pretreatment effectively alleviated behavioral impairments, reduced neutrophil aggregation, and suppressed neuroinflammation in the brain by regulating TREM2/NF-κB/NLRP3 pathways after intraventricular LPS injection. These findings provide novel insights into the potent protective effects of DHE as a promising novel TREM2 agonist against LPS-induced neuroinflammation, revealing its potential therapeutic role in the treatment of central nervous system diseases associated with neuroinflammation.

Keywords: 19,20-Dehydroervatamine; NF-κB; NLRP3; Neuroinflammation; TREM2.