Interferon-γ (IFN-γ) is involved in normal neurodevelopment and pathological neuroinflammation. However, it is still unclear whether boosting neuronal IFN-γ signaling could affect neural repair and what is the functional downstream of IFN-γ in neurons. Here we showed that deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a previously reported immunosuppressor gene, could maintain the activation of IFN-γ-STAT1 signaling in neurons and promote retinal ganglion cell (RGC) axon regeneration. The IFN-γ induced regeneration did not require the known regeneration-associated factors such as mTOR or STAT3 and could synergize with Pten/Socs3 deletion to achieve rapid and long-distance axon regeneration. We further identified that the cGAMP synthase (cGAS)–stimulator of interfe...[ Read more ]

Interferon-γ (IFN-γ) is involved in normal neurodevelopment and pathological neuroinflammation. However, it is still unclear whether boosting neuronal IFN-γ signaling could affect neural repair and what is the functional downstream of IFN-γ in neurons. Here we showed that deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a previously reported immunosuppressor gene, could maintain the activation of IFN-γ-STAT1 signaling in neurons and promote retinal ganglion cell (RGC) axon regeneration. The IFN-γ induced regeneration did not require the known regeneration-associated factors such as mTOR or STAT3 and could synergize with Pten/Socs3 deletion to achieve rapid and long-distance axon regeneration. We further identified that the cGAMP synthase (cGAS)–stimulator of interferon genes (STING) pathway was the functional downstream signaling of IFN-γ in RGCs. Injection of cGAMP could directly promote RGC axon regeneration. In peripheral, but not central nervous system, IFN-γ was secreted by injured axons and then upregulated cGAS expression in Schwann cells and blood cells. cGAS produced cGAMP in sciatic nerve and promoted peripheral axon regeneration. Our data demonstrated how the anti-viral mechanism in neurons regulated axon growth and provided novel targets to enhance neural regeneration.