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Published on: January 30, 2014
Nicotinamide mononucleotide mitigates neuroinflammation by enhancing GPX4-mediated ferroptosis defense in microglia
Ruiqiong Su1, Xiaoyue Pan1, Qiuyuan Chen1
1Ningxia Key Laboratory of Cerebrocranial Diseases, School of Basic Medical Science, Ningxia Medical University, Yinchuan 750004, China.
Background:
Numerous neurological diseases involving neuroinflammation, particularly microglia, contribute to neuronal death. Ferroptosis is implicated in various diseases characterized by neuronal injury. Studies showed that nicotinamide mononucleotide (NMN) inhibits both neuroinflammation and ferroptosis. However, the mechanisms of NMN in both ferroptosis and neuroinflammation remain unclear. We aimed to explore the effects of NMN on neuroinflammation and the susceptibility of microglia to ferroptosis.
Methods:
Ferroptosis markers in macroglia exposed to lipopolysaccharides (LPS) were analyzed using CCK8, flow cytometry, ELISA, and quantitative RT-PCR. The effects of NMN on LPS-induced ferroptosis in microglia were evaluated through flow cytometry, western blot, and immunofluorescence staining. RT-PCR analysis assessed the inflammatory cytokine production of microglia subjected to Ferrostatin-1-regulated ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-involved microglia ferroptosis under LPS induction. In BV2 microglia, an inhibitor of GPX4, RSL3, was employed to suppress GPX4 expression. Intracerebroventricular injection of LPS was performed to evaluate neuroinflammation and microglia activation in vivo.
Results:
NMN effectively rescued LPS-induced ferroptosis and improved cell viability in microglia. Co-administration of NMN and ferrostatin-1 significantly reduced proinflammatory cytokine production in microglia following the introduction of LPS stimuli. Mechanistically, NMN facilitated glutathione (GSH) production, and enhanced resistance to lipid peroxidation occurred in a manner dependent on GPX4, repressing cytokine transcription and protecting cells from ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-associated microglia ferroptosis under LPS induction. Furthermore, simultaneous injection of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains. The data from the present study indicated that NMN enhances GPX4-mediated ferroptosis defense against LPS-induced ferroptosis in microglia by recruiting GSH, thereby inhibiting neuroinflammation.
Conclusion:
Therapeutic approaches to effectively target ferroptosis in diseases using NMN, consideration should be given to both its anti-ferroptosis and anti-inflammatory effects to attain optimal outcomes, presenting promising strategies for treating neuroinflammation-related diseases or disorders.
Insights
Nicotinamide mononucleotide (NMN) protects microglia from ferroptosis and reduces neuroinflammation by enhancing glutathione production and GPX4 activity. This dual action offers a promising therapeutic strategy for neurological disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neuroinflammation, particularly involving microglia, is a key driver of neuronal death in many neurological diseases.
- Ferroptosis, a form of regulated cell death, is increasingly implicated in conditions associated with neuronal injury.
- Nicotinamide mononucleotide (NMN) has shown potential in inhibiting both neuroinflammation and ferroptosis, but its precise mechanisms require further elucidation.
Purpose of the Study:
- To investigate the effects of NMN on neuroinflammation and microglia susceptibility to ferroptosis.
- To elucidate the underlying molecular mechanisms by which NMN influences these processes.
Main Methods:
- Assessed ferroptosis markers in lipopolysaccharide (LPS)-stimulated microglia using CCK8, flow cytometry, ELISA, and RT-PCR.
- Evaluated NMN's impact on LPS-induced ferroptosis in microglia via flow cytometry, western blot, and immunofluorescence.
- Utilized RNA sequencing to uncover NMN's mechanism in microglia ferroptosis and assessed in vivo effects of NMN on LPS-induced neuroinflammation in mouse brains.
Main Results:
- NMN treatment significantly improved microglia viability and rescued LPS-induced ferroptosis.
- NMN enhanced glutathione (GSH) production and GPX4-dependent resistance to lipid peroxidation, thereby repressing pro-inflammatory cytokine production.
- In vivo administration of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains.
Conclusions:
- NMN demonstrates a dual therapeutic effect by inhibiting ferroptosis and neuroinflammation in microglia.
- NMN enhances GPX4-mediated ferroptosis defense in microglia through GSH recruitment, consequently suppressing neuroinflammation.
- NMN presents a promising therapeutic strategy for neuroinflammation-related diseases, warranting consideration of its anti-ferroptosis and anti-inflammatory properties.
