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Activation of an innate immunity signaling pathway promotes axonal regeneration



Damage to the central nervous system (CNS) usually leads to permanent paralysis and sensory impairment. The peripheral nervous system (PNS), on the other hand, is able to regenerate axons after nerve lesions and often enables at least partial restoration of function. In recent years, research into the molecular mechanisms underlying these differences has focused on the immune system, including recently the cGAS-STING signaling pathway, which involves cyclic GMP-AMP synthase (cGAS) and its receptor, the 'stimulator of interferon genes' (STING), but also ciliary neurotrophic factor (CNTF) and the transcription factor STAT3.


In their search for key factors in axon regeneration, Wang and colleagues screened for phosphatases in peripheral neurons after axotomy. Among other things, they discovered the protein tyrosine phosphatase non-receptor type 2 (PTPN2). The elimination or pharmacological inhibition of this enzyme led to increased axon growth in nerve cells that form the optic nerve. The research team then investigated the signaling pathways in which PTPN2 is involved.


Following transcriptome analysis, the elimination of this phosphatase in sensory dorsal root ganglia showed in particular an increase in the expression of interferon-stimulated genes. In follow-up experiments, the authors were able to demonstrate that interferon γ (IFNγ) positively influences axon regeneration of retinal ganglion cells in the absence of PTPN2. Naturally occurring IFNγ in the vitreous of the eye proved to be a decisive factor in promoting regeneration, as the blockade of interferon receptors delayed the axonal growth process.


To further clarify the role of IFNγ in promoting regeneration, the researchers isolated retinal ganglion cells after retrograde labeling of their axons. The interferon-dependent genes were significantly upregulated by the addition of IFNγ in PTPN2-deficient cells, and there was a sustained activation of phosphorylated STAT1. Furthermore, the CNTF- and PTEN-dependent signaling pathways were also found to be involved in promoting axonal repair via their respective effectors STAT3 and mTOR separately from the IFNγR-STAT1 axis.


In further studies, Wang et al. focused on the cGAS-STING signaling pathway, as cGAS, which recognizes double-stranded DNA and initiates cGAMP synthesis to activate STING, is regulated by STAT1. After nerve injury, some of the axotomized optic neurons exhibited DNA damage, which was more detectable in the absence of PTPN2, and knockdown of cGAS or STING prevented the promotion of axon regeneration.


Finally, the peripheral nervous system (PNS) was also examined in the study. Here, nerve injury specifically triggered the production and local synthesis of IFNγ within axons. In contrast to CNS neurons, Schwann cells and some blood cells showed induced cGAS activity. These cells produced cGAMP, which enabled communication with neuronal STING through a transcellular mechanism. The authors showed that the activation of cGAS-STING is significantly involved in the modulation of regeneration-associated genes (RAGs) and the formation of microtubules and can thus promote axon regeneration.


However, it should be emphasized that the interplay between axon regeneration and neuroimmunity is extremely complex and not yet fully understood, so that a therapeutic use of these findings is not expected in the near future.


References:


Jiang M, Zeng W (2023) Antiviral immunity rewired for axon regeneration. Cell Reports Medicine 4:100907


Wang X, Yang C, Wang X, ..., Zhang ZY, Liu K (2023) Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis. Neuron 111:236


Image credit: iStock/Ralwel

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