Blocking the EGFR/p38/NF-κB signaling pathway alleviates disruption of BSCB and subsequent inflammation after spinal cord injury

• Published in: Neurochemistry international 2021-11, Vol.150, p.105190-105190, Article 105190
• Main Authors: Li, Zai-Wang, Zhao, Jing-Jing, Li, Su-Ya, Cao, Ting-Ting, Wang, Yi, Guo, Yi, Xi, Guang-Jun
• Format: Article
• Language: English
• Subjects: Animals; Blood spinal cord barrier; Cells, Cultured; Endothelium, Vascular - metabolism; Epidermal growth factor receptor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Female; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Secondary inflammatory injury; Signal Transduction - physiology; Spinal Cord - blood supply; Spinal Cord - metabolism; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - prevention & control; Spinal cord injury; Thoracic Vertebrae - injuries
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2021.105190

Epidermal growth factor receptor (EGFR) activation is involved in blood spinal cord barrier (BSCB) disruption and secondary injury after spinal cord injury (SCI). However, the underlying mechanisms of EGFR activation mediating BSCB disruption and secondary injury after SCI remain unclear. An in vitro model of oxygen and glucose deprivation/reoxygenation (OGD/R) induced BSCB damage and in vivo rat SCI model were employed to define the role of EGFR/p38/NF-κB signal pathway activation and its induced inflammatory injury in main cellular components of BSCB. Genetic regulation (lentivirus delivered shRNA and overexpression system) or chemical intervention (agonist or inhibitor) were applied to activate or inactivate EGFR and p38 in astrocytes and microvascular endothelial cells (MEC) under which conditions, the expression of pro-inflammatory factors (TNF-α, iNOS, COX-2, and IL-1β), tight junction (TJ) protein (ZO-1 and occludin), nuclear translocation of NF-κB and permeability of BSCB were analyzed. The pEGFR was increased in astrocytes and MEC which induced the activation of EGFR and p38 and NF-κB nuclear translocation. The activation of EGFR and p38 increased the TNF-α, iNOS, COX-2, and IL-1β responsible for the inflammatory injury and reduced the ZO-1 and occludin which caused BSCB disruption. While EGFR or p38 inactivation inhibited NF-κB nuclear translocation, and markedly attenuated the production of pro-inflammatory factors and the loss of TJ protein. This study suggests that the EGFR activation in main cellular components of BSCB after SCI mediates BSCB disruption and secondary inflammatory injury via the EGFR/p38/NF-κB pathway. •Epidermal growth factor receptor (EGFR) phosphorylation is the main event in BSCB after SCI.•pEGFR in astrocytes and microvascular endothelial cells after SCI mediates BSCB disruption and secondary inflammatory injury.•EGFR/p38/NF-κB signaling pathway activation after SCI contributes to the regulation of BSCB TJ integrity.