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Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation
1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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.
Insights
Dehydroervatamine (DHE) activates TREM2, reducing neuroinflammation by suppressing pro-inflammatory cytokines and restoring mitochondrial function. This natural alkaloid shows promise as a therapeutic agent for central nervous system diseases.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia are key players in neuroinflammation, with dual roles in debris clearance and cytokine release.
- TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is crucial in modulating microglial inflammatory responses.
- Neuroinflammatory disorders affect millions globally, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the potential of Dehydroervatamine (DHE), a natural alkaloid, in mitigating microglial inflammatory phenotypes and neuroinflammation.
- To elucidate the mechanism of DHE's action, particularly its interaction with TREM2 and downstream signaling pathways.
Main Methods:
- In vitro studies using LPS-stimulated BV2 microglial cells to assess DHE's effects on cytokine production, mitochondrial function, and inflammasome activation.
- TREM2 gene silencing experiments to confirm the role of TREM2 in DHE's anti-inflammatory effects.
- In vitro co-culture models (SH-SY5Y neuroblastoma cells with BV2 microglia) to evaluate DHE's neuroprotective capacity.
- In vivo studies using a zebrafish model to assess DHE's effects on behavior, neutrophil aggregation, and neuroinflammation following LPS injection.
Main Results:
- DHE directly binds to and activates TREM2, suppressing pro-inflammatory cytokine production in microglial cells.
- DHE restores mitochondrial function and inhibits NLRP3 inflammasome activation via the TREM2/DAP12 pathway.
- TREM2 silencing abrogated DHE's suppressive effects on neuroinflammation and related pathways.
- DHE demonstrated neuroprotective effects in vitro and alleviated behavioral deficits and neuroinflammation in vivo.
- DHE regulated TREM2/NF-κB/NLRP3 pathways in both in vitro and in vivo models.
Conclusions:
- DHE acts as a novel TREM2 agonist, effectively suppressing LPS-induced neuroinflammation.
- DHE exhibits significant neuroprotective properties by modulating microglial activation and inflammatory signaling.
- DHE holds therapeutic potential for central nervous system diseases characterized by neuroinflammation.
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