Morozzi Giulio, Rothen Julian, Toussaint Gauthier, De Lange Katrina, Westritschnig Katrin, Doelemeyer Arno, Ueberschlag Vanessa Pitiot, Kahle Peter, Lambert Christian, Obrecht Michael, Beckmann Nicolau, Ritter Veronique, Panesar Moh, Stauffer Daniela, Garnier Isabelle, Mueller Matthias, Guerini Danilo, Keller Caroline Gubser, Knehr Judith, Roma Guglielmo, Bidinosti Michael, Brachat Sophie, Morvan Frederic, Fornaro Mara
Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
iScience. 2021 Nov 14;24(12):103434. doi: 10.1016/j.isci.2021.103434. eCollection 2021 Dec 17.
Inflammatory responses are crucial for regeneration following peripheral nerve injury (PNI). PNI triggers inflammatory responses at the site of injury. The DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) sense foreign and self-DNA and trigger type I interferon (IFN) immune responses. We demonstrate here that following PNI, the cGAS/STING pathway is upregulated in the sciatic nerve of naive rats and dysregulated in old rats. In a nerve crush mouse model where STING is knocked out, myelin content in sciatic nerve is increased resulting in accelerated functional axon recovery. STING KO mice have lower macrophage number in sciatic nerve and decreased microglia activation in spinal cord 1 week post injury. STING activation regulated processing of colony stimulating factor 1 receptor (CSF1R) and microglia survival . Taking together, these data highlight a previously unrecognized role of STING in the regulation of nerve regeneration.
炎症反应对于周围神经损伤（PNI）后的再生至关重要。PNI在损伤部位引发炎症反应。DNA传感受体环鸟苷酸-腺苷酸合成酶（cGAS）及其下游效应物干扰素基因刺激因子（STING）可感知外来和自身DNA，并触发I型干扰素（IFN）免疫反应。我们在此证明，PNI后，cGAS/STING通路在未受伤大鼠的坐骨神经中上调，而在老年大鼠中失调。在STING基因敲除的神经挤压小鼠模型中，坐骨神经中的髓磷脂含量增加，导致功能性轴突恢复加速。STING基因敲除小鼠在损伤后1周坐骨神经中的巨噬细胞数量减少，脊髓中的小胶质细胞激活减少。STING激活调节集落刺激因子1受体（CSF1R）的加工和小胶质细胞存活。综上所述，这些数据突出了STING在神经再生调节中以前未被认识的作用。
