Citation

4749 total record number 121 records this year

The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity

Wang, XF;Vigouroux, R;Syonov, M;Baglaenko, Y;Nikolakopoulou, AM;Ringuette, D;Rus, H;DiStefano, PV;Dufour, S;Shabanzadeh, AP;Lee, S;Mueller, BK;Charish, J;Harada, H;Fish, JE;Wither, J;Wälchli, T;Cloutier, JF;Zlokovic, BV;Carlen, PL;Monnier, PP;

Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences BCB-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 BCB-integrity. To study BCB-integrity, we developed light-sheet imaging for three-dimensional analysis. We show that liver- or muscle-specific knockout of Hfe2/Rgmc induces BCB-breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits in mice. 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, triggering BCB-disruption. HFE2 administration in female mice with experimental autoimmune encephalomyelitis, a model for multiple sclerosis, prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BCB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BCB-dysfunction.