title: Claudin-1 induced sealing of blood-brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis.
abstract: In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), loss of the blood-brain barrier (BBB) tight junction (TJ) protein claudin-3 correlates with immune cell infiltration into the CNS and BBB leakiness. Here we show that sealing BBB TJs by ectopic tetracycline-regulated expression of the TJ protein claudin-1 in Tie-2 tTA//TRE-claudin-1 double transgenic C57BL/6 mice had no influence on immune cell trafficking across the BBB during EAE and furthermore did not influence the onset and severity of the first clinical disease episode. However, expression of claudin-1 did significantly reduce BBB leakiness for both blood borne tracers and endogenous plasma proteins specifically around vessels expressing claudin-1. In addition, mice expressing claudin-1 exhibited a reduced disease burden during the chronic phase of EAE as compared to control littermates. Our study identifies BBB TJs as the critical structure regulating BBB permeability but not immune cell trafficking into CNS during EAE, and indicates BBB dysfunction is a potential key event contributing to disease burden in the chronic phase of EAE. Our observations suggest that stabilizing BBB barrier function by therapeutic targeting of TJs may be beneficial in treating MS, especially when anti-inflammatory treatments have failed.
authors: Theodor Kocher Institute, University of Bern, Switzerland.
authors: Friederike
authors: F
authors: Pfeiffer
authors: Julia
authors: J
authors: Schäfer
authors: Ruth
authors: R
authors: Lyck
authors: Victoria
authors: V
authors: Makrides
authors: Sarah
authors: S
authors: Brunner
authors: Nicole
authors: N
authors: Schaeren-Wiemers
authors: Urban
authors: U
authors: Deutsch
authors: Britta
authors: B
authors: Engelhardt
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology* / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002490:Central Nervous System / Q000503:physiopathology; D062445:Claudin-1; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000503:physiopathology*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D019108:Tight Junctions / Q000502:physiology*
chemical_list: D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins; D042787:Receptor, TIE-2; D013752:Tetracycline