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


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.



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

10020_2013_1901149_MOESM1_ESM.pdf (2 mb)
Supplementary material, approximately 2.03 MB.


  1. 1.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. (2000) Multiple sclerosis. N. Engl. J. Med. 343:938–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Hafler DA, et al. (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357:851–62.CrossRefPubMedGoogle Scholar
  3. 3.
    Weber F, et al. (2008) IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun. 9:259–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Caillier SJ, et al. (2008) Uncoupling the roles of HLA-DRB1 and HLA-DRB5 genes in multiple sclerosis. J. Immunol. 181:5473–80.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bennett J, et al. (2010) Blood-brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE. J. Neuroimmunol. 229:180–91.CrossRefGoogle Scholar
  6. 6.
    Neuwelt EA. (2004) Mechanisms of disease: the blood-brain barrier. Neurosurgery. 54:131–40; discussion 141–2.CrossRefPubMedGoogle Scholar
  7. 7.
    Kebir H, et al. (2007) Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 13:1173–5.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yu F, Kamada H, Niizuma K, Endo H, Chan PH. (2008) Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J. Neurotrauma. 25:184–95.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Annunziata P, Cioni C, Santonini R, Paccagnini E. (2002) Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium. J. Neuroimmunol. 131:41–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Koltzenburg M. (2004) The role of TRP channels in sensory neurons. Novartis Found. Symp. 260:206–13; discussion 213–20, 277–9.PubMedGoogle Scholar
  11. 11.
    Caterina MJ, et al. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 389:816–24.CrossRefGoogle Scholar
  12. 12.
    Patwardhan AM, et al. (2010) Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents. J. Clin. Invest.120:1617–26.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bohlen CJ, et al. (2010) A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell. 141:834–45.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Razavi R, et al. (2006) TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell. 127:1123–35.CrossRefPubMedGoogle Scholar
  15. 15.
    Kimball ES, Wallace NH, Schneider CR, D’Andrea MR, Hornby PJ. (2004) Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice. Neurogastroenterol. Motil. 16:811–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Szabo A, et al. (2005) Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice. J. Pharmacol. Exp. Ther. 314:111–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Mezey E, et al. (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl. Acad. Sci. U. S. A. 97:3655–60.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Doly S, Fischer J, Salio C, Conrath M. (2004) The vanilloid receptor-1 is expressed in rat spinal dorsal horn astrocytes. Neurosci. Lett. 357:123–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Roberts JC, Davis JB, Benham CD. (2004) [3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution. Brain Res. 995:176–83.CrossRefPubMedGoogle Scholar
  20. 20.
    Toth A, et al. (2005) Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res. Mol. Brain Res. 135:162–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Cristino L, et al. (2006) Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. 139:1405–15.CrossRefGoogle Scholar
  22. 22.
    Schilling T, Eder C. (2009) Importance of the non-selective cation channel TRPV1 for microglial reactive oxygen species generation. J. Neuroimmunol. 216:118–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Hu DE, Easton AS, Fraser PA. (2005) TRPV1 activation results in disruption of the blood-brain barrier in the rat. Br. J. Pharmacol. 146:576–84.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Beggs S, Liu XJ, Kwan C, Salter MW. (2010) Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Mol. Pain. 6:74.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Musumeci G, et al. (2011) Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-alpha and of IL-1beta in experimental autoimmune encephalomyelitis. Neurobiol. Dis. 43:669–77.CrossRefPubMedGoogle Scholar
  26. 26.
    DeLuca GC, et al. (2007) An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proc. Natl. Acad. Sci. U. S. A. 104:20896–901.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ramagopalan SV, et al. (2007) Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol. 6:604–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Sadovnick AD, Risch NJ, Ebers GC. (1998) Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method. Canadian Collaborative Study Group. Can. J. Neurol. Sci. 25:216–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Dorfman R, Tsui H, Salter MW, Dosch HM. (2010) TRPV1 Genetics. In: Vanilloid Receptor TRPV1 in Drug Discovery. Arthur G, Faltinek CR (eds.) J Wiley & Sons, Hoboken, NJ, pp. 134–149.CrossRefGoogle Scholar
  30. 30.
    Kuwabara T, et al. (2009) CCR7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells. J. Immunol. 183:2513–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Luo Y, Fischer FR, Hancock WW, Dorf ME. (2000) Macrophage inflammatory protein-2 and KC induce chemokine production by mouse astrocytes. J. Immunol. 165:4015–23.CrossRefPubMedGoogle Scholar
  32. 32.
    Winer S, et al. (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15:921–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Aulchenko YS, et al. (2008) Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis. Nat. Genet. 40:1402–3.CrossRefPubMedGoogle Scholar
  34. 34.
    Purcell S, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81:559–75.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Arima Y, et al. (2012) Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148:447–57.CrossRefPubMedGoogle Scholar
  36. 36.
    Schellenberg AE, Buist R, Yong VW, Del Bigio MR, Peeling J. (2007) Magnetic resonance imaging of blood-spinal cord barrier disruption in mice with experimental autoimmune encephalomyelitis. Magn. Reson. Med. 58:298–305.CrossRefPubMedGoogle Scholar
  37. 37.
    Akbar A, et al. (2008) Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 57:923–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Martelli L, et al. (2007) A potential role for the vanilloid receptor TRPV1 in the therapeutic effect of curcumin in dinitrobenzene sulphonic acid-induced colitis in mice. Neurogastroenterol. Motil. 19:668–74.CrossRefPubMedGoogle Scholar
  39. 39.
    Basu S, Srivastava P. (2005) Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells. Proc. Natl. Acad. Sci. U. S. A. 102:5120–5.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    O’Connell PJ, Pingle SC, Ahern GP. (2005) Dendritic cells do not transduce inflammatory stimuli via the capsaicin receptor TRPV1. FEBS Lett. 579:5135–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Winer S, et al. (2001) Type I diabetes and multiple sclerosis patients target islet plus central nervous system autoantigens; nonimmunized nonobese diabetic mice can develop autoimmune encephalitis. J. Immunol. 166:2831–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Butterfield RJ, et al. (1998) New genetic loci that control susceptibility and symptoms of experimental allergic encephalomyelitis in inbred mice. J. Immunol. 161:1860–7.PubMedGoogle Scholar
  43. 43.
    Butterfield RJ, et al. (1999) Genetic analysis of disease subtypes and sexual dimorphisms in mouse experimental allergic encephalomyelitis (EAE): relapsing/remitting and monophasic remitting/nonrelapsing EAE are immunogenetically distinct. J. Immunol. 162:3096–102.PubMedGoogle Scholar
  44. 44.
    Khairatkar-Joshi N, Szallasi A. (2009) TRPV1 antagonists: the challenges for therapeutic targeting. Trends Mol. Med. 15:14–22.CrossRefPubMedGoogle Scholar
  45. 45.
    International Multiple Sclerosis Genetics C. (2011) Genome-wide association study of severity in multiple sclerosis. Genes Immun. 12:615–25.CrossRefGoogle Scholar
  46. 46.
    Cunningham S, Patterson CC, McDonnell G, Hawkins S, Vandenbroeck K. (2005) Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis. Genes Immun. 6:265–70.CrossRefPubMedGoogle Scholar
  47. 47.
    Cunningham S, et al. (2007) The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(AD-CYAP1), and susceptibility to multiple sclerosis. J. Neuroimmunol. 183:208–13.CrossRefPubMedGoogle Scholar
  48. 48.
    Marrosu MG, et al. (2002) Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study. Lancet. 359:1461–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Herculano-Houzel S. (2011) Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution. PLoS One. 6:e17514.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Van Buren JJ, Bhat S, Rotello R, Pauza ME, Premkumar LS. (2005) Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol. Pain. 1:17.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Sathianathan V, et al. (2003) Insulin induces cobalt uptake in a subpopulation of rat cultured primary sensory neurons. Eur. J. Neurosci. 18:2477–86.Google Scholar
  52. 52.
    Baker D, et al. (2001) Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15:300–2.CrossRefPubMedGoogle Scholar
  53. 53.
    Loria F, et al. (2008) Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide. Eur. J. Neurosci. 28:633–41.CrossRefPubMedGoogle Scholar
  54. 54.
    Cristino L, et al. (2008) Immunohistochemical localization of anabolic and catabolic enzymes for anandamide and other putative endovanilloids in the hippocampus and cerebellar cortex of the mouse brain. Neuroscience. 151:955–68.CrossRefPubMedGoogle Scholar
  55. 55.
    De Petrocellis L, Davis JB, Di Marzo V. (2001) Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett. 506:253–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Starowicz K, Cristino L, Di Marzo V. (2008) TRPV1 receptors in the central nervous system: potential for previously unforeseen therapeutic applications. Curr. Pharm. Des. 14:42–54.CrossRefPubMedGoogle Scholar
  57. 57.
    Szallasi A, Cortright DN, Blum CA, Eid SR. (2007) The vanilloid receptor TRPV1:10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug. Discov. 6:357–72.CrossRefPubMedGoogle Scholar
  58. 58.
    Gunthorpe MJ, Chizh BA. (2009) Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov. Today. 14:56–67.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2013

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

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

Personalised recommendations