PDF(Pubmed)
Abstract：
Spinal cord injury (SCI) can prompt an immediate disruption to the blood-spinal cord barrier (BSCB). Restoring the integrity of this barrier is vital for the recovery of neurological function post-SCI. The UTX protein, a histone demethylase, has been shown in previous research to promote vascular regeneration and neurological recovery in mice with SCI. However, it is unclear whether UTX knockout could facilitate the recovery of the BSCB by reducing its permeability. In this study, we systematically studied BSCB disruption and permeability at different time points after SCI and found that conditional UTX deletion in endothelial cells (ECs) can reduce BSCB permeability, decrease inflammatory cell infiltration and ROS production, and improve neurological function recovery after SCI. Subsequently, we used RNA sequencing and ChIP-qPCR to confirm that conditional UTX knockout in ECs can down-regulate expression of myosin light chain kinase (MLCK), which specifically mediates myosin light chain (MLC) phosphorylation and is involved in actin contraction, cell retraction, and tight junctions (TJs) protein integrity. Moreover, we found that MLCK overexpression can increase the ratio of p-MLC/MLC, further break TJs, and exacerbate BSCB deterioration. Overall, our findings indicate that UTX knockout could inhibit the MLCK/p-MLC pathway, resulting in decreased BSCB permeability, and ultimately promoting neurological recovery in mice. These results suggest that UTX is a promising new target for treating SCI.
摘要：
脊髓损伤（SCI）可以立即破坏血液脊髓屏障（BSCB）。恢复该屏障的完整性对于SCI后神经功能的恢复至关重要。UTX蛋白，组蛋白去甲基酶,在先前的研究中已显示出促进SCI小鼠的血管再生和神经恢复。然而,目前尚不清楚UTX敲除是否可以通过降低BSCB的渗透性来促进BSCB的恢复。在这项研究中,我们系统地研究了SCI后不同时间点的BSCB破坏和通透性，发现内皮细胞（ECs）中条件UTX缺失可以降低BSCB通透性，减少炎症细胞浸润和ROS产生，改善SCI后神经功能恢复。随后，我们使用RNA测序和ChIP-qPCR证实条件UTX敲除ECs可以下调肌球蛋白轻链激酶(MLCK)的表达,特异性介导肌球蛋白轻链（MLC）磷酸化并参与肌动蛋白收缩，细胞回缩,和紧密连接（TJs）蛋白质完整性。此外，我们发现MLCK过表达可以增加p-MLC/MLC的比例，进一步打破TJ，并加剧BSCB恶化。总的来说,我们的发现表明UTX敲除可以抑制MLCK/p-MLC途径，导致BSCB渗透率下降，并最终促进小鼠的神经系统恢复。这些结果表明UTX是治疗SCI的有希望的新靶标。
