Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model

Neural Regen Res, 2025 · DOI: https://doi.org/10.4103/NRR.NRR-D-23-01925 · Published: March 1, 2025

Simple Explanation

This study investigates the role of SHP2, a protein involved in inflammation, in secondary inflammation following spinal cord injury (SCI). It found that SHP2 is highly expressed in microglia at the injury site. The researchers inhibited SHP2 expression using siRNA and SHP2 inhibitors, which attenuated the microglial inflammatory response in a lab model. Mice treated with SHP2 inhibitors showed improved hind limb function and reduced bladder issues after SCI. Further experiments revealed that inhibiting SHP2 promoted M2 polarization (anti-inflammatory) and inhibited M1 polarization (pro-inflammatory) in microglia. Additionally, blocking SHP2 mitigated neuronal apoptosis caused by inflammatory factors released by microglia.

Study Duration

2 weeks

Participants

40 male adult (6–8 weeks of age) C57BL/6 mice

Evidence Level

Level II: Animal study

Key Findings

1
SHP2 expression is upregulated in microglia at the site of spinal cord injury and in LPS-induced microglia.
2
Inhibiting SHP2 attenuates inflammation in an in vitro model of spinal cord injury by reducing M1-related inflammatory markers and increasing M2-related anti-inflammatory markers.
3
SHP2 inhibition reduces tissue damage after spinal cord injury, facilitating functional recovery, as evidenced by improved BBB scores, reduced residual urine volume, and improved motor function in mice treated with the SHP2 inhibitor NSC87877.

Research Summary

This study investigates the role of SHP2 in secondary inflammation following spinal cord injury (SCI). The researchers found that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. The key findings include that SHP2 expression is upregulated in microglia at the injury site, and inhibiting SHP2 attenuates inflammation by reducing M1 markers and increasing M2 markers. In vivo experiments showed that SHP2 inhibition reduces tissue damage and facilitates functional recovery, as indicated by improved BBB scores and motor function. Transcriptome sequencing revealed a correlation between SHP2 and pathways related to inflammation and energy metabolism.

Practical Implications

Therapeutic Target

SHP2 represents a potential therapeutic target for reducing secondary inflammation and promoting functional recovery after spinal cord injury.

Microglial Polarization Modulation

Modulating microglial polarization by inhibiting SHP2 can shift the microglial phenotype from pro-inflammatory (M1) to anti-inflammatory (M2), thus reducing neuronal damage.

Novel Therapeutic Approach

SHP2 inhibitors could provide a novel therapeutic approach for spinal cord injury treatment by targeting inflammation and promoting tissue repair.

Study Limitations

1
The SCI microenvironment undergoes extremely complex changes that cannot be fully simulated by in vitro inflammation models or understood by assessing cell–cell interactions
2
It was difficult to ensure that the impact to the spinal cord was consistently delivered at the same location in the mouse SCI model, which may have led to slight intra-group variations in the data.
3
SHP2 inhibitors are still in the preclinical stage, and their biotoxicity, cellular targeting, and applications still need to be investigated in depth.

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