Claudin-1 impairs blood–brain barrier by downregulating endothelial junctional proteins in traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability in patients. Brain microvasculature endothelial cells form the blood-brain barrier (BBB) which functions to maintain a protective barrier for the brain from the passive entry of systemic solutes. As a result of the cellular disruption caused by TBI, the BBB is compromised. Tight junction disruption in the endothelium of the BBB has been implicated in this response, but the underlying mechanisms remain unresolved. We utilized various <i>in vivo</i> models of severe to mild TBI as well as <i>in vitro</i> exposure of brain endothelial cells (bEND.3) to analyze conditions encountered following TBI to gain mechanistic insight into alterations observed at the BBB. We found that claudin-1 (CLDN1), was significantly increased in the brain endothelium both <i>in vivo</i> and <i>in vitro</i>. The observed increase of CLDN1 expression correlated with down-regulation of claudin-5 (CLDN5), occludin (OCLN), and zonula occludens (ZO-1), thereby altering BBB integrity by decreasing TEER and increasing permeability. Knockdown of CLDN1 in these pathogenic conditions showed stability of the endothelial junctional proteins. A decline in the epigenetic regulator silent information regulator family protein 1 (SIRT1), a member of the NAD+ dependent protein deacetylases, coincided with this upregulation of CLDN1. Indeed, the quenching of oxidative stress through NAC treatment was able to reduce injury-induced upregulation of CLDN1 <i>in vitro</i>. Mechanistically, an SRC-dependent tyrosine phosphorylation of OCLN and ZO-1 in CLDN1-modulated conditions was observed. Our findings will provide new insights into BBB deregulation and new possible treatment opportunities for TBI.