Nrf2 regulates ICAM-1-mediated neutrophil extracellular trap formation after traumatic brain injury.

Traumatic brain injury (TBI) triggers secondary neurovascular damage characterized by oxidative stress, blood-brain barrier (BBB) disruption, and neuroinflammation, leading to long-term cognitive deficits. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant defense, but its role in maintaining neurovascular integrity after TBI remains unclear. Here, using in vivo fluid percussion injury in wild-type, Nrf2-/-, and ICAM-1-/- mice, and in vitro stretch injury in human brain microvascular endothelial cells (hBMVECs), we demonstrate that TBI suppresses Nrf2 signaling, reducing antioxidant gene expression, and increasing oxidative and nitrosative stress. Nrf2 impairment enhances BBB permeability, ICAM-1-mediated leukocyte transmigration and promotes neutrophil extracellular trap (NET) formation. ICAM-1 deletion rescues these effects, confirming the mechanistic link between Nrf2, ICAM-1, and immune-mediated vascular damage. Preservation of Nrf2 signaling maintains antioxidant defenses, limits immune cell infiltration, and restricts NET-mediated injury. Importantly, Nrf2 deficiency impairs functional recovery, whereas its presence correlates with improved neurological outcomes. Targeting the Nrf2-ICAM-1 axis may reduce immune-mediated neurovascular injury, limit NET formation, and improve functional recovery after traumatic brain injury.