Study on MERTK Reducing Blood-Spinal Cord Barrier Permeability after Spinal Cord Injury via RhoA/ROCK1/p-MLC Pathway

Spinal Cord Injury (SCI) is a central nervous system disease caused by trauma, inflammation, tumors, or other pathological reasons, resulting in sensory, motor, and autonomic nervous system dysfunction in patients, imposing a heavy burden on individuals and society. The disruption of the Blood-Spinal Cord Barrier (BSCB) that occurs with spinal cord injury is a key event in secondary injury. MERTK plays an important role in regulating inflammation and cell skeleton dynamics, but its specific role in BSCB is not yet clear. This study reveals the unique role of MERTK in BSCB repair. MERTK expression is reduced in vascular endothelial cells after SCI. By upregulating tight junction proteins (TJs), overexpression of MERTK reduced BSCB permeability, thereby inhibiting inflammation and apoptosis. Ultimately, this led to enhanced neuroregeneration and functional recovery. Further experiments revealed that the RhoA/ROCK1/p-MLC pathway plays a key role in the effects of MERTK. These findings highlight the role of MERTK in promoting SCI recovery through its ability to alleviate BSCB permeability and may provide potential targets for SCI repair.

Research Background and Objectives

The incidence of SCI is increasing year by year worldwide, but effective treatment methods are still limited so far. Secondary injury encompasses various processes such as inflammatory response, tissue edema, neuronal degeneration, and glial scar formation. Hemorrhage and BSCB disruption caused by primary injury are considered important events in the development of secondary injury.

BSCB, as a special filter, controls the transfer of metabolites, nutrients, and oxygen between blood and spinal cord, maintaining a stable internal environment, which is crucial for protecting the spinal cord. Its disruption can lead to the infiltration of blood cells such as neutrophils and macrophages into the spinal cord tissue, releasing inflammatory molecules, triggering inflammatory responses, inducing oxidative stress, and triggering neuronal apoptosis. Therefore, inhibiting BSCB disruption and preventing subsequent apoptosis may be an important therapeutic approach to reduce the severity of SCI and promote functional recovery.

MERTK is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, which plays a key role in maintaining adult tissue homeostasis. The precise role of this family of receptors in SCI is still not fully understood. The relationship between MERTK and inflammation has been associated with the nervous system in diseases such as multiple sclerosis, subarachnoid hemorrhage, and traumatic brain injury. Inflammation is closely related to BSCB permeability and can activate microglia, leading to the release of inflammatory mediators and upregulation of TJs. Based on these findings, MERTK may play a role in reducing inflammation and apoptosis, promoting nerve repair while maintaining BSCB integrity.

Research Source and Author Information

This study was received on September 23, 2023, and published on December 22, 2023, in Neurosci. Bull. by Lin Jiezhao, Sun Yuanfang, Xia Bin, Wang Yihan, Xie Changnan, Wang Jinfeng, Hu Jinwei, and Zhu Lixin from the Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.

Research Methods and Results

This study designed various experimental procedures including cell culture, animal models, behavioral tests, histological staining, Western blot, immunofluorescence staining, TUNEL staining, and BSCB permeability tests. By establishing SCI models and oxygen-glucose deprivation (OGD) induced BEND.3 cell models, the differential expression and cellular localization of MERTK were determined. The results showed that MERTK protein expression decreased after SCI and exhibited a similar temporal expression pattern to TJs. The role of MERTK in BSCB is thought to be through downregulating TJs, reducing BSCB permeability, thereby indirectly inhibiting inflammation and apoptosis, leading to enhanced functional recovery and neuroregeneration.

Further experiments using the BEND.3 cell model confirmed that MERTK upregulates the expression of TJs. Under OGD conditions, the expression of tight junction proteins decreased, while MERTK overexpression could reverse this effect. MERTK overexpression inhibited inflammation in the early stages after SCI, reducing levels of inflammatory cytokines. In addition, MERTK overexpression could also reduce apoptosis.

Behavioral tests showed that MERTK overexpression promoted neuroregeneration and functional recovery in animal models. Immunofluorescence staining and NISSL staining results indicated that overexpressing MERTK increased the number of neurons and reduced tissue damage. In Western blot analysis, overexpression of MERTK significantly increased the protein expression of GAP43 and NF200.

Moreover, the research data showed that MERTK reduces the increased BSCB permeability due to SCI by inhibiting the RhoA/ROCK1/p-MLC pathway. This mechanism may involve remodeling of the cell skeleton, affecting the structure of tight junction proteins and maintaining the integrity of BSCB.

Research Conclusions and Value

This study reveals for the first time the key role of MERTK in maintaining BSCB structural integrity, alleviating inflammation and apoptosis in the repair process after spinal cord injury, providing a biological basis and targets for further in-depth study of MERTK’s role in SCI pathological mechanisms and its therapeutic potential. The study found that overexpression of MERTK can protect BSCB structural integrity, reduce inflammation and apoptosis, and promote functional recovery and neuroregeneration by inhibiting the RhoA/ROCK1/p-MLC pathway. Considering that MERTK’s kinase activity is easily regulated, this finding contributes to the clinical translation of experimental results.