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

iScience, 2021 · DOI: https://doi.org/10.1016/j.isci.2021.103434 · Published: December 17, 2021

Simple Explanation

This study investigates the role of the STING pathway in nerve regeneration after peripheral nerve injury (PNI). The researchers found that the cGAS/STING pathway is upregulated in the sciatic nerve following nerve injury. They used STING knockout mice and observed increased myelin content and accelerated functional axon recovery after sciatic nerve crush. STING KO mice also showed reduced macrophage numbers and decreased microglia activation. In vitro experiments revealed that STING activation regulates the processing of CSF1R, a receptor crucial for microglia survival. These findings suggest STING plays a significant role in nerve regeneration regulation.

Study Duration

Not specified

Participants

Young (2 months) and old rats (19 months), young and old wild-type C57BL/6 (WT) and C57BL/6J-Tmem173gt/J mice (STING KO)

Evidence Level

Not specified

Key Findings

1
The cGAS/STING pathway is upregulated in the sciatic nerve after PNI and is dysregulated in aged rats, suggesting a role in the inflammatory response to nerve injury.
2
Genetic ablation of STING in mice resulted in increased myelin content in the sciatic nerve and accelerated functional axon recovery after nerve crush injury.
3
STING KO mice exhibited reduced macrophage numbers in the sciatic nerve and decreased microglia activation in the spinal cord following nerve injury.

Research Summary

This study investigates the role of the cGAS/STING pathway in peripheral nerve injury (PNI) and regeneration. The study found that the cGAS/STING pathway is upregulated in the sciatic nerve following nerve injury and is dysregulated in aged rats. Using STING knockout mice, the researchers observed increased myelin content and accelerated functional axon recovery after sciatic nerve crush (SNC). STING KO mice also showed reduced macrophage numbers in the sciatic nerve and decreased microglia activation in the spinal cord following injury. In vitro experiments indicated that STING activation regulates the processing of colony stimulating factor 1 receptor (CSF1R) and microglia survival. These findings highlight a previously unrecognized role of STING in the regulation of nerve regeneration.

Practical Implications

Therapeutic Target

Modulating STING activity could be a potential therapeutic strategy for promoting nerve regeneration and improving outcomes after peripheral nerve injury.

Aging-Related Decline

The dysregulation of the cGAS/STING pathway with age suggests that targeting this pathway could help to improve nerve regeneration in elderly individuals.

Microglia Modulation

Understanding the role of STING in microglia activation may lead to new approaches for managing neuropathic pain and neurodegeneration associated with nerve injuries.

Study Limitations

1
It was not possible to directly measure cytosolic DNA or cGAMP in sciatic nerve of mice subjected to SNC or sham-operated animals.
2
Detection of cytosolic DNA in small tissue samples and measurements of cGAMP in a complex biological matrix is still a signiﬁcant challenge in the ﬁeld.
3
The downstream mechanisms underlying how STING signaling regulates preservation of myelin and microglia activation remain to be further elucidated.

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