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A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration
Meng-Meng Jin1,2,3, Fen Wang4, Di Qi4
1Department of Neurology, Suzhou Clinical Research Center of Neurological Disease, Suzhou Municipal Hospital of Nanjing Medical University, Suzhou, China.
Abstract:
Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker (iNOS/NO, IL-1β, and IL-6) expression and reduction of M2 marker (Arginase1, Ym1/2, and IL-10) were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α. Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated when Atg5 knockdown in BV2 cells but alleviated when microglia pretreatment with rapamycin. Activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation as the AKT specific inhibitor perifosine prevented the increase of LC3II (an autophagic marker) in TNF-α stimulated microglia. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.
Insights
Tumor necrosis factor-alpha (TNF-α) impairs microglia autophagy, promoting neuroinflammation linked to Parkinson's disease. Enhancing autophagy shifts microglia to an anti-inflammatory state, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neuroinflammation and autophagy dysfunction are implicated in neurodegenerative diseases like Parkinson's disease (PD).
- The precise role of autophagy in microglia polarization and its impact on neuroinflammation remains unclear.
- Tumor necrosis factor-alpha (TNF-α) is a key mediator of neuroinflammation in PD and is toxic to dopaminergic neurons.
Purpose of the Study:
- To investigate the effect of TNF-α on autophagy in microglia.
- To determine how autophagy influences microglia polarization and neuroinflammation.
- To explore the potential of modulating autophagy as a therapeutic strategy for PD-related neuroinflammation.
Main Methods:
- Microglia were challenged with TNF-α to assess autophagic flux and M1/M2 polarization markers.
- Autophagy was modulated using serum deprivation, pharmacologic activators (rapamycin, resveratrol), and inhibitors (3-MA, Atg5 siRNA).
- Neurotoxicity was evaluated using conditioned media from treated microglia on neuronal cells.
- AKT/mTOR signaling pathway involvement was examined using specific inhibitors.
Main Results:
- TNF-α impaired autophagic flux in microglia, leading to M1 pro-inflammatory polarization and reduced M2 anti-inflammatory markers.
- Enhancing autophagy (via rapamycin, resveratrol) promoted M2 polarization and suppressed M1 markers.
- Inhibiting autophagy aggravated TNF-α-induced M1 polarization; Atg5 knockdown alone induced M1 status.
- TNF-α-induced microglia conditioned media exhibited neurotoxicity, exacerbated by Atg5 knockdown and reduced by rapamycin.
- AKT/mTOR signaling inhibition partially reversed TNF-α-induced autophagy impairment.
Conclusions:
- TNF-α inhibits microglia autophagy via the AKT/mTOR pathway, driving M1 polarization and neuroinflammation.
- Autophagy enhancement promotes microglia polarization towards an M2 phenotype, resolving inflammation.
- Modulating microglia autophagy presents a promising therapeutic avenue for neuroinflammatory conditions like Parkinson's disease.
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