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

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

  • Neuron. 2022 Nov 4;S0896-6273(22)00961-8. doi: 10.1016/j.neuron.2022.10.028.
Xu Wang 1,  Chao Yang 1,  Xuejie Wang 2,  Jinmin Miao 3,  Weitao Chen 4,  Yiren Zhou 5,  Ying Xu 6,  Yongyan An 5,  Aifang Cheng 7,  Wenkang Ye 7,  Mengxian Chen 5,  Dong Song 6,  Xue Yuan 8,  Jiguang Wang 6,  Peiyuan Qian 7,  Angela Ruohao Wu 9,  Zhong-Yin Zhang 3,  Kai Liu 10
Affiliations

Affiliations

  • 1 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China; Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China; Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou 510515, China.
  • 2 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 3 Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.
  • 4 Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
  • 5 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 6 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 7 Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China; Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 8 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 9 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China; Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China; Center for Aging Science, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 10 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China; Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China; Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 36370710 DOI: 10.1016/j.neuron.2022.10.028
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).

Keywords

PTPN2; STAT1; axon regeneration; cGAS-STING; dorsal root ganglions; interferon gamma; optic nerve injury; retinal ganglion cells.

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