Netrin‐1 protects blood–brain barrier (BBB) integrity after cerebral ischemia‐reperfusion by activating the Kruppel‐like factor 2 (KLF2)/occludin pathway

Abstract

Ischemia/reperfusion (I/R)‐induced neural damage and neuroinflammation have been associated with pathological progression during stroke. Netrin‐1 is an important member of the family of laminin‐related secreted proteins, which plays an important role in governing axon elongation. However, it is unknown whether Netrin‐1 possesses a beneficial role in stroke. Here, we employed the middle cerebral artery occlusion (MCAO) model to study the function of Netrin‐1 in alleviating brain injuries. Our results demonstrate that Netrin‐1 rescued poststroke neurological deficits and inhibited production of the inflammatory cytokines such as interleukin 6 (IL‐6) and endothelial chemokine (C‐X‐C motif) ligand 1 (Cxcl1). Importantly, Netrin‐1 protected against MCAO‐induced dysfunction of the blood–brain barrier (BBB) in mice and a reduction in the expression of the tight junction (TJ) protein occludin. Additionally, we report that Netrin‐1 could ameliorate oxygen‐glucose deprivation/reoxygenation (OGD/R)‐induced injury and prevent aggravation in endothelial monolayer permeability in bEnd.3 human brain microvascular endothelial cells (HBMVECs). Mechanistically, Netrin‐1 ameliorated OGD/R‐induced decrease in occludin and Kruppel‐like factor 2 (KLF2) in HBMVECs. Notably, silencing of KLF2 abolished the beneficial effects of Netrin‐1 in protecting endothelial permeability and occludin expression, suggesting that these effects are mediated by KLF2. In conclusion, our findings suggest that Netrin‐1 could constitute a novel therapeutic strategy for ischemic stroke.

The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies

“…These and other modifications [ 220 ] are mediated by different signalling pathways (relevant for normal and pathological conditions) and strongly point at a regulatory function, e.g., via interaction with claudins and/or ZO proteins ( Figure 2 D) [ 205 ]. The number of studies that exploit these pathways for new medical applications is increasing [ 141 , 221 ]. There is wide agreement that occludin is involved in the regulation of the TJ permeability [ 212 , 222 ].…”