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Molecular Medicine

, Volume 19, Issue 1, pp 149–159 | Cite as

TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

  • Geoffrey Paltser
  • Xue Jun Liu
  • Jason Yantha
  • Shawn Winer
  • Hubert Tsui
  • Ping Wu
  • Yuko Maezawa
  • Lindsay S. Cahill
  • Christine L. Laliberté
  • Sreeram V. Ramagopalan
  • Gabriele C. DeLuca
  • A. Dessa Sadovnick
  • Igor Astsaturov
  • George C. Ebers
  • R. Mark Henkelman
  • Michael W. Salter
  • H.-Michael Dosch
Research Article

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.

Notes

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (CIHR), the MS Society of the United Kingdom, and the MS Society of Canada Scientific Research Foundation. We thank L Morikawa for excellent assistance with histopathology. G Paltser is a recipient of awards from CIHR and the Banting and Best Diabetes Centre (Toronto). LS Cahill is a recipient of a CIHR postdoctoral fellowship.

Supplementary material

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Authors and Affiliations

  • Geoffrey Paltser
    • 1
    • 2
  • Xue Jun Liu
    • 1
    • 3
  • Jason Yantha
    • 1
    • 2
  • Shawn Winer
    • 1
    • 2
  • Hubert Tsui
    • 1
    • 2
  • Ping Wu
    • 1
    • 2
  • Yuko Maezawa
    • 1
    • 2
  • Lindsay S. Cahill
    • 4
  • Christine L. Laliberté
    • 4
  • Sreeram V. Ramagopalan
    • 5
  • Gabriele C. DeLuca
    • 5
  • A. Dessa Sadovnick
    • 6
  • Igor Astsaturov
    • 7
  • George C. Ebers
    • 5
  • R. Mark Henkelman
    • 4
  • Michael W. Salter
    • 1
    • 3
  • H.-Michael Dosch
    • 1
    • 2
  1. 1.Neuroscience and Mental Health Program, Research InstituteThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Departments of Immunology and PediatricsUniversity of TorontoTorontoCanada
  3. 3.Department of PhysiologyUniversity of TorontoTorontoCanada
  4. 4.Mouse Imaging CentreThe Hospital for Sick ChildrenTorontoCanada
  5. 5.Wellcome Trust Centre for Human Genetics and Department of Clinical NeurologyUniversity of OxfordOxfordUK
  6. 6.Department of Medical Genetics and Faculty of Medicine, Division of NeurologyUniversity of British ColumbiaVancouverCanada
  7. 7.Program in Developmental TherapeuticsFox Chase Cancer CenterPhiladelphiaUSA

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