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

ABSTRACT: The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote axon regeneration after injury, independent of mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STINGs) activation is the functional downstream signaling. Directly activating neuronal STING by cGAMP promotes axon regeneration. In contrast to the central axons, IFNγ is locally translated in the injured peripheral axons and upregulates cGAS expression in Schwann cells and infiltrating blood cells to produce cGAMP, which promotes spontaneous axon regeneration as an immunotransmitter. Our study demonstrates that injured peripheral nervous system (PNS) axons can direct the environmental innate immune response for self-repair and that the neural antiviral mechanism can be harnessed to promote axon regeneration in the central nervous system (CNS).

SUBMITTER: Wang X

PROVIDER: S-EPMC9851977 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Wang Xu X Yang Chao C Wang Xuejie X Miao Jinmin J Chen Weitao W Zhou Yiren Y Xu Ying Y An Yongyan Y Cheng Aifang A Ye Wenkang W Chen Mengxian M Song Dong D Yuan Xue X Wang Jiguang J Qian Peiyuan P Wu Angela Ruohao AR Zhang Zhong-Yin ZY Liu Kai K

Neuron 20221111 2

The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote axon regeneration after injury, independent of mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STINGs) activation is the functional downstream signaling. Directly activating neuronal ST ...[more]

PMID: 36370710

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Project description:Schizophrenia is a severe neuropsychiatric disorder affecting about 1% of individuals worldwide. Increased innate immune activation and neuronal apoptosis are common findings in schizophrenia. Interferon beta (IFN-β), an essential cytokine in promoting and regulating innate immune responses, causes neuronal apoptosis in vitro. However, the precise pathogenesis of schizophrenia is unknown. Recent studies indicate that a domesticated endogenous retroviral envelope glycoprotein of the W family (HERV-W ENV, also called ERVWE1 or syncytin 1), derived from the endogenous retrovirus group W member 1 (ERVWE1) locus on chromosome 7q21.2, has a high level in schizophrenia. Here, we found an increased serum IFN-β level in schizophrenia and showed a positive correlation with HERV-W ENV. In addition, serum long intergenic non-protein coding RNA 1930 (linc01930), decreased in schizophrenia, was negatively correlated with HERV-W ENV and IFN-β. In vitro experiments showed that linc01930, mainly in the nucleus and with noncoding functions, was repressed by HERV-W ENV through promoter activity suppression. Further studies indicated that HERV-W ENV increased IFN-β expression and neuronal apoptosis by restraining the expression of linc01930. Furthermore, HERV-W ENV enhanced cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes protein (STING) expression and interferon regulatory factor 3 (IRF3) phosphorylation in neuronal cells. Notably, cGAS interacted with HERV-W ENV and triggered IFN-β expression and neuronal apoptosis caused by HERV-W ENV. Moreover, Linc01930 participated in the increased neuronal apoptosis and expression level of cGAS and IFN-β induced by HERV-W ENV. To summarize, our results suggested that linc01930 and IFN-β might be novel potential blood-based biomarkers in schizophrenia. The totality of these results also showed that HERV-W ENV facilitated antiviral innate immune response, resulting in neuronal apoptosis through the linc01930/cGAS/STING pathway in schizophrenia. Due to its monoclonal antibody GNbAC1 application in clinical trials, we considered HERV-W ENV might be a reliable therapeutic choice for schizophrenia.

Dataset Information

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

Publications

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

Similar Datasets

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