Netrin 1 regulates blood–brain barrier function and neuroinflammation

Abstract

Blood–brain barrier function is driven by the influence of astrocyte-secreted factors. During neuroinflammatory responses the blood–brain barrier is compromised resulting in central nervous system damage and exacerbated pathology. Here, we identified endothelial netrin 1 induction as a vascular response to astrocyte-derived sonic hedgehog that promotes autocrine barrier properties during homeostasis and increases with inflammation. Netrin 1 supports blood–brain barrier integrity by upregulating endothelial junctional protein expression, while netrin 1 knockout mice display disorganized tight junction protein expression and barrier breakdown. Upon inflammatory conditions, blood–brain barrier endothelial cells significantly upregulated netrin 1 levels in vitro and in situ, which prevented junctional breach and endothelial cell activation. Finally, netrin 1 treatment during experimental autoimmune encephalomyelitis significantly reduced blood–brain barrier disruption and decreased clinical and pathological indices of disease severity. Our results demonstrate that netrin 1 is an important regulator of blood–brain barrier maintenance that protects the central nervous system against inflammatory conditions such as multiple sclerosis and experimental autoimmune encephalomyelitis. Astrocyte-derived Sonic Hedgehog helps to maintain the integrity of the blood-brain barrier, but many of its downstream effectors are unknown. Podjaski et al. show that in multiple sclerosis, Sonic Hedgehog upregulates netrin-1 expression on the CNS vasculature, inducing an autocrine response that reduces blood-brain barrier permeability and dampens neuroinflammation.