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Editor-in-charge | Xi
Damage to the central nervous system may result in permanent loss
of sensory and motor function.
For example, after spinal cord injury, the nerve axons that the brain projects long distances to the spinal cord are ruptured, and the axons that are broken in the central nervous system cannot regenerate, eventually leading to permanent functional damage
to the central nervous system.
Since axons in the spinal cord generally do not die after their corresponding neurons in the brain are damaged, promoting axon regeneration is a research direction
that may treat spinal cord injury.
In contrast to the central nervous system, peripheral nerves have a strong regenerative ability after injury and can restore some of their functions
to a certain extent.
The process of nerve damage and repair can activate the immune system and immune-related cytokines, but it is not entirely clear how these immune-related signaling pathways affect post-injury neurons and whether they directly promote axon regeneration
.
On November 11, 2022, Liu Kai's research group of the Hong Kong University of Science and Technology published a long article "Driving Axon Regeneration by Orchestrating Neuronal and Non-neuronal Innate Immune Responses via the" in Neuron IFNγ-cGAS-STING Axis, found that by knocking out PTPN2 and adding type II interferon stimulated genes (ISGs) in neurons including the cGAS-STING pathway, it was possible to activate interferon stimulated genes (ISGs).
Thus promoting axon regeneration
in the central nervous system.
Because previous studies have shown that some phosphatases have an inhibitory effect on axon regeneration, the researchers first knocked down 84 phosphatase genes in Dorsal root ganglion, (DRG) neurons cultured in vitro to screen for phosphatases that might inhibit axon regeneration
。 The experimental results showed that knocking down PTPN2 could significantly increase the length
of DRG neurites cultured in vitro.
In vivo experiments, knocking out PTPN2 of retinal ganglion cells (RGC) of the central nervous system can also enhance axon regeneration
of RGCs to a certain extent.
Since previous studies have shown that PTPN2 can inhibit the activation pathway of multiple cytokines, the researchers continue to explore whether adding cytokines while knocking out PTPN2 can further enhance axon regeneration
.
The results showed that knockout PTPN2 could work synergistically with the addition of IFNγ to further increase the number and growth rate of regenerated axons, and its regenerative role depended on interferon-gamma receptors (IFNGRs) and STAT1 signaling pathway
of neurons 。 In wild-type RGCs, STAT1 activation downstream of IFNγ injection lasted only one day, while STAT1 activation in PTPN2-knocked neurons lasted for nearly a week
.
Combining activation of the IFNγ-STAT1 pathway with other signaling pathways known to promote axon regeneration allows faster and more distant pivotal axon regeneration
to be observed.
The above results suggest that activating ISG in RGCs promotes axon regeneration
.
The researchers further explored which downstream pathway of IFNγ-STAT1 is directly involved in the axon regeneration process
.
cGAS-STING is a pathway
that recognizes DNA within cells to regulate autoimmunity.
cGAS begins to synthesize cGAMP (cyclic GMP-AMP) after binding to the DNA of its own or foreign pathogen, and cGAMP can bind and activate the linker protein STING, which further activates TBK1 and IRF3
.
Immunostaining of retinal sections showed significant elevation
of cGAS expression in RGCs in the PTPN2 KO+IFNγ-treated group.
DNA damage caused by PTPN2 knockout and nerve damage activates cGAS
in RGC.
Knockout of cGAS or STING inhibits axon regeneration
caused by PTPN2 KO+IFNγ.
Direct injection of the STING agonist cGAMP into the vitreous body of mouse eyes can also directly promote nerve regeneration
.
These results suggest that the cGAS-STING signaling pathway mediates axonal regeneration
triggered by PTPN2 KO+IFNγ.
The researchers further focused on whether the IFNγ-cGAS-STING signaling pathway is involved in the self-repair process
of peripheral nerves.
Unlike central nervous system injury, peripheral nerves spontaneously produce IFNγ through axonal local translation after injury and release it into the injury area
.
Knocking down IFNγ in DRG or local injection of IFNGR neutralizing antibodies at the site of injury can inhibit spontaneous regeneration
of peripheral axons.
IFNγ released by axons increases cGAS expression in Schwann cells and blood cells in the injured zone, resulting in cGAMP to promote peripheral nerve regeneration
.
cGAMP can directly stimulate the axons of in vitro cultured DRG neurons and enhance their axon growth
.
In summary, this study shows that peripheral nerve axons can directly regulate the immune response in their injured environment after injury to promote self-repair, while artificial activation of the IFNγ-cGAS-STING signaling pathway in the central nervous system can also promote axon regeneration
in the central nervous system.
The study also suggests that the immune response after nervous system injury may simultaneously complete the functions
of fighting invading pathogens and promoting nerve repair.
The study was co-first authors Dr.
Xu Wang and Chao Yang, as well as Professor Zhong-Yin Zhang of the University of Purdue, Professor Ruohao Wu, Professor Peiyuan Qian, Professor Jiguang Wang of the Hong Kong University of Science and Technology
, and other collaborators.
Original link:
https://doi.
org/10.
1016/j.
neuron.
2022.
10.
028
Platemaker: Eleven
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