title: TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis.
abstract: Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1-/- B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.
authors.affiliation: Neuroscience and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Paltser
authors.forename: Xue Jun
authors.initials: XJ
authors.lastname: Liu
authors.forename: Jason
authors.initials: J
authors.lastname: Yantha
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.forename: Hubert
authors.initials: H
authors.lastname: Tsui
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maezawa
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Cahill
authors.forename: Christine L
authors.initials: CL
authors.lastname: Laliberté
authors.forename: Sreeram V
authors.initials: SV
authors.lastname: Ramagopalan
authors.forename: Gabriele C
authors.initials: GC
authors.lastname: DeLuca
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
authors.forename: George C
authors.initials: GC
authors.lastname: Ebers
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: H-Michael
authors.initials: HM
authors.lastname: Dosch
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D037342:Pertussis Toxin; D020641:Polymorphism, Single Nucleotide; D013116:Spinal Cord / Q000473:pathology / Q000502:physiology; D013154:Spleen / Q000166:cytology; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D037342:Pertussis Toxin