The liver and muscle secreted Hfe2-protein maintains blood brain barrier integrity

Liver failure causes blood-brain-barrier (BBB) breakdown leading to central nervous system damage, however the mechanisms whereby the liver influences BBB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BBB integrity. We developed light-sheet imaging for three-dimensional study of BBB function. We show that liver- or muscle-specific knockout of Hfe2 induces BBB breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits. In healthy animals, soluble Hfe2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells and the ensuing BBB disruption. Hfe2 administration in an animal model of multiple sclerosis prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BBB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BBB dysfunction such as multiple sclerosis.