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

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 2; pp. 236 - 255.e7
• Main Authors: Wang, Xu, Yang, Chao, Wang, Xuejie, Miao, Jinmin, Chen, Weitao, Zhou, Yiren, Xu, Ying, An, Yongyan, Cheng, Aifang, Ye, Wenkang, Chen, Mengxian, Song, Dong, Yuan, Xue, Wang, Jiguang, Qian, Peiyuan, Wu, Angela Ruohao, Zhang, Zhong-Yin, Liu, Kai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.01.2023
• Subjects: axon regeneration; Axons - physiology; cGAS-STING; dorsal root ganglions; Immunity, Innate; interferon gamma; Nerve Regeneration - physiology; Nucleotidyltransferases - metabolism; optic nerve injury; PTPN2; retinal ganglion cells; Retinal Ganglion Cells - physiology; STAT1; interferon gamma; STAT1; axon regeneration; optic nerve injury; retinal ganglion cells; cGAS-STING; PTPN2; dorsal root ganglions
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.10.028

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). [Display omitted] •Neuronal Ptpn2 deletion amplifies the IFNγ response to promote CNS axon regeneration•The cGAS-STING pathway is the functional downstream of IFNγ•Injured DRG axons release IFNγ that elevates cGAS in Schwann cells and blood cells The neural innate immune responses for axon regeneration is not well understood. Wang and Yang et al. demonstrate that activating the immune signaling IFNγ-cGAS-STING axis promotes axon regeneration in both the PNS and the CNS, uncovering a role for the antiviral machinery in neural repair.