Inhibition of UTX/KDM6A improves recovery of spinal cord injury by attenuating BSCB permeability and macrophage infiltration through the MLCK/p‑MLC pathway

Journal of Neuroinflammation, 2023 · DOI: https://doi.org/10.1186/s12974-023-02936-1 · Published: October 18, 2023

Simple Explanation

Spinal cord injury (SCI) can disrupt the blood–spinal cord barrier (BSCB). Restoring the BSCB is crucial for neurological recovery after SCI. This study investigates how a protein called UTX affects BSCB permeability and recovery after SCI in mice. The study found that deleting UTX in endothelial cells reduced BSCB permeability, decreased inflammatory cell infiltration, lowered ROS production, and improved neurological function recovery after SCI in mice. Researchers discovered that UTX knockout could inhibit the MLCK/p-MLC pathway, leading to decreased BSCB permeability and ultimately promoting neurological recovery in mice, suggesting UTX as a potential target for SCI treatment.

Study Duration

56 Days

Participants

Female C57BL/6J mice aged 8 to 12 weeks

Evidence Level

Not specified

Key Findings

1
Conditional UTX deletion in endothelial cells reduces BSCB permeability, decreases inflammatory cell infiltration and ROS production, and improves neurological function recovery after SCI.
2
Conditional UTX knockout in ECs can down-regulate expression of myosin light chain kinase (MLCK), which specifically mediates myosin light chain (MLC) phosphorylation.
3
MLCK overexpression can increase the ratio of p-MLC/MLC, further break TJs, and exacerbate BSCB deterioration.

Research Summary

This study investigates the role of UTX in regulating BSCB permeability following SCI. The findings reveal that conditional ablation of UTX in ECs reduces vascular permeability and enhances neurological recovery. The study uncovers that UTX ablation can impede the expression of myosin light-chain kinase (MLCK), which is involved in endothelial myosin light chain (MLC) phosphorylation, leading to actomyosin contractility and increased BSCB permeability. UTX ablation attenuates BSCB permeability by inhibiting the MLCK/p-MLC pathway, thus preserving the integrity of endothelial cell TJs. This study presents a new theoretical framework for SCI management and neurological function restoration.

Practical Implications

Therapeutic Target

UTX is identified as a promising therapeutic target for treating spinal cord injury.

New Framework

The study presents a novel theoretical framework for managing SCI and restoring neurological function.

Vascular Stability

UTX plays a crucial role in regulating vascular stability and reducing BSCB permeability after SCI.

Study Limitations

1
The study is limited to a mouse model of SCI.
2
Further research is needed to explore the clinical implications of UTX inhibition in humans.
3
The specific mechanisms by which UTX interacts with MLCK require further investigation.

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