Dataset Information

STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia.

ABSTRACT: 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 in vitro. Taking together, these data highlight a previously unrecognized role of STING in the regulation of nerve regeneration.

SUBMITTER: Morozzi G

PROVIDER: S-EPMC8633968 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia.

Morozzi Giulio G Rothen Julian J Toussaint Gauthier G De Lange Katrina K Westritschnig Katrin K Doelemeyer Arno A Ueberschlag Vanessa Pitiot VP Kahle Peter P Lambert Christian C Obrecht Michael M Beckmann Nicolau N Ritter Veronique V Panesar Moh M Stauffer Daniela D Garnier Isabelle I Mueller Matthias M Guerini Danilo D Keller Caroline Gubser CG Knehr Judith J Roma Guglielmo G Bidinosti Michael M Brachat Sophie S Morvan Frederic F Fornaro Mara M

iScience 20211114 12

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. I ...[more]

PMID: 34877494

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Project description:BackgroundG-CSF has been shown to increase neuronal survival, which may positively influence the spinal cord microenvironment during the course of muscular dystrophies.Methodology/principal findingsMale MDX mice that were six weeks of age received a left sciatic nerve transection and were treated with intraperitoneal injections of 200 µg/kg/day of G-CSF 7 days before and 7 days after the transection. The axotomy was performed after the cycles of muscular degeneration/regeneration, consistent with previous descriptions of this model of muscular dystrophy. C57BL/10 mice were used as control subjects. Seven days after the surgery, the animals were sacrificed and their lumbar spinal cords were processed for immunohistochemistry (anti-MHC I, anti-Synaptophysin, anti-GFAP and anti-IBA-1) and transmission electron microscopy. MHC I expression increased in both strains of mice after the axotomy. Nevertheless, the MDX mice displayed a significantly smaller MHC I upregulation than the control mice. Regarding GFAP expression, the MDX mice showed a stronger astrogliosis compared with the C57BL/10 mice across all groups. Both groups that were treated with G-CSF demonstrated preservation of synaptophysin expression compared with the untreated and placebo groups. The quantitative analysis of the ultrastructural level showed a preservation of the synaptic covering for the both groups that were treated with G-CSF and the axotomized groups showed a smaller loss of synaptic contact in relation to the treated groups after the lesion.Conclusions/significanceThe reduction of active inputs to the alpha-motoneurons and increased astrogliosis in the axotomized and control groups may be associated with the cycles of muscle degeneration/regeneration that occur postnatally. The G-CSF treated group showed a preservation of the spinal cord microenvironment after the lesion. Moreover, the increase of MHC I expression in the MDX mice that were treated with G-CSF may indicate that this drug performs an active role in regenerative potential after lesions.

Dataset Information

STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia.

Publications

STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia.

Similar Datasets

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