Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis

Wang, Xu; Yang, Chao; Wang, Xuejie; Miao, Jiangyong; Chen, Weitao; Zhou, Yiren; Xu, Ying; An, Yongyan; Cheng, Aifang; Ye, Wenkang; Chen, Mengxian; Dong, Song; Yang, Xue; Wang, Ji‐Guang; Qian, Pei‐Yuan; Wu, Sean M.; Zhang, Zhong-Yin; Liu, Kai

doi:10.1016/j.neuron.2022.10.028

Cited by 36 publications

(18 citation statements)

References 89 publications

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“…In the present study, we found that metformin noticeably alleviated the behavior dysfunction and DA neuron loss in PD model mice, companied by reduced the accumulation of senescent astrocytes and inactivation of astrocytic cGAS-STING in SNpc. cGAS-STING, components of the innate immune system, is involved in neuroinflammation and cellular senescence [ 46 – 48 ]. Here, we observed that astrocytic cGAS deletion reversed the protective effects of metformin on astrocyte senescence and neurodegeneration in PD model mice.…”

Section: Discussionmentioning

confidence: 99%

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Wang,

Tian,

Zhou

et al. 2024

J Neuroinflammation

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Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. Methods Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. Results We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. Conclusions This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Wang,

Tian,

Zhou

et al. 2024

J Neuroinflammation

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“…To search for the molecular targets in axon regeneration, Wang and colleagues carried out a functional screening utilizing the DRG replating assay. 1 Out of 84 pre-selected phosphatases, protein tyrosine phosphatase non-receptor type 2 ( Ptpn2 ) was identified among 5 candidates, knockdown of which promoted axon regrowth. Of particular importance, RGCs showed more regenerating axons post nerve injury when PTPN2 was inhibited pharmacologically or abrogated genetically.…”

Section: Main Textmentioning

confidence: 99%

“… In Neuron ’s January 18 th issue, Wang et al. 1 report that activating the immune signaling IFNγ-cGAS-STING axis promotes axon regeneration in both the peripheral and central nervous systems. Their findings uncover the coordination mechanism of neural innate immune responses for axon regeneration.…”

mentioning

confidence: 99%

Antiviral immunity rewired for axon regeneration

Jiang

Zeng

2023

Cell Reports Medicine

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“…In addition, a recent study showed an mTOR-independent mechanism used by protein tyrosine phosphatase non-receptor type 2 (PTPN2) to control axonal regeneration. In PTPN2 knockout mice, the DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated and triggers the expression of interferon-stimulated genes (ISGs) in neurons, which ultimately promotes axon regeneration in the central nervous system [ 85 ].…”

Section: Roles Of Protein Phosphatases In Regenerationmentioning

confidence: 99%

The Emerging Role of Protein Phosphatase in Regeneration

Zhang

Liu

Zhao

et al. 2023

Life

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Maintaining normal cellular behavior is essential for the survival of organisms. One of the main mechanisms to control cellular behavior is protein phosphorylation. The process of protein phosphorylation is reversible under the regulation of protein kinases and protein phosphatases. The importance of kinases in numerous cellular processes has been well recognized. In recent years, protein phosphatases have also been demonstrated to function actively and specifically in various cellular processes and thus have gained more and more attention from researchers. In the animal kingdom, regeneration frequently occurs to replace or repair damaged or missing tissues. Emerging evidence has revealed that protein phosphatases are crucial for organ regeneration. In this review, after providing a brief overview of the classification of protein phosphatases and their functions in several representative developmental processes, we highlight the critical roles that protein phosphatases play in organ regeneration by summarizing the most recent research on the function and underlying mechanism of protein phosphatase in the regeneration of the liver, bone, neuron, and heart in vertebrates.

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Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis

Cited by 36 publications

References 89 publications

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Antiviral immunity rewired for axon regeneration

The Emerging Role of Protein Phosphatase in Regeneration

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