TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

Paltser, Geoffrey; Liu, Xue Jun; Yantha, Jason; Winer, Shawn; Tsui, Hubert; Wu, Ping; Maezawa, Yoshiro; Cahill, Lindsay S.; Laliberté, Christine; Ramagopalan, Sreeram; DeLuca, Gabriele C.; Sadovnick, A. Dessa; Astsaturov, Igor; Ebers, George C.; Henkelman, R. Mark; Salter, Michael W.; Hm, Dosch

doi:10.2119/molmed.2012.00329

Cited by 24 publications

(24 citation statements)

References 60 publications

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“…1F, G). Similar to that described for other TRP channel deficiencies (18)(19)(20), TRPM8 2/2 mice exhibited a modest, albeit significant, reduction in EAE severity, which suggests a proinflammatory rather than anti-inflammatory role for this channel in the context of T cell-driven neuroinflammation ( Fig. 1G).…”

Section: Resultssupporting

confidence: 75%

“…After inoculation, myelin-reactive CD4 + T-cell populations are expanded in the periphery and promote MS-like leukocytic infiltration and demyelination in the CNS, which leads to progressive ascending paresis and paralysis of the mouse (17). Several TRP channels have been implicated in neuroinflammation, as demonstrated by attenuated EAE progression in mice with deficiencies in TRPM4, TRPM2, and TRPV1 (18)(19)(20). In this study, we aimed to investigate the therapeutic value of icilin treatment during autoimmune-driven neuroinflammation using the EAE model, hypothesizing that an anti-inflammatory phenotype could be driven by TRPM8 channel activation.…”

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confidence: 99%

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The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T‐cell response

et al. 2018

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The synthetic supercooling drug, icilin, and its primary receptor target, the cation channel transient receptor potential (TRP) melastatin-8 (TRPM8), have been described as potent negative regulators of inflammation in the colon. The aim of this study was to determine whether the anti-inflammatory action of icilin could potentially be used to treat autoimmune neuroinflammatory disorders, such as multiple sclerosis (MS). During experimental autoimmune encephalomyelitis (EAE)-a CD4 T cell-driven murine model of MS-we found that both wild-type (WT) and TRPM8-deficient EAE mice were protected from disease progression during icilin treatment, as evidenced by delays in clinical onset and reductions in neuroinflammation. In vitro, icilin potently inhibited the proliferation of murine and human CD4 T cells, with the peripheral expansion of autoantigen-restricted T cells similarly diminished by the administration of icilin in mice. Attenuation of both TRPM8 and TRP ankyrin-1 T-cell proliferation by icilin was consistent with the WT phenotype, which suggests a mechanism that is independent of these channels. In addition, icilin treatment altered the expressional profile of activated CD4 T cells to one that was indicative of restricted effector function and limited neuroinflammatory potential. These findings identify a potent anti-inflammatory role for icilin in lymphocyte-mediated neuroinflammation and highlight clear pleiotropic effects of the compound beyond classic TRP channel activation.-Ewanchuk, B. W., Allan, E. R. O., Warren, A. L., Ramachandran, R., Yates, R. M. The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response.

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Section: Resultssupporting

confidence: 75%

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confidence: 99%

The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T‐cell response

et al. 2018

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“…TRPVs are found to play an important role in immune regulation and various pathophysiological processes. TRPV1 has been attributed to the majority of immunoregulatory responses [43,[69][70][71][72][73][74][75] whereas few reports are available on TRPV4 along with other TRPs and altered immune responses in experimental immunobiological investigations [49,[76][77][78]. Together, it appears that these TRPVs are mostly involved in immunogenic responses associated with autoimmunity, inflammatory responses, and with various attributes related to disease biology.…”

Section: Discussionmentioning

confidence: 99%

Functional expression of TRPV channels in T cells and their implications in immune regulation

et al. 2015

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The importance of Ca 2+ signalling and temperature in the context of T cell activation is well known. However, the molecular identities of key players involved in such critical regulations are still unknown. In this work we explored the endogenous expression of transient receptor potential vanilloid (TRPV) channels, a group of thermosensitive and non-selective cation channels, in T cells. Using flow cytometry and confocal microscopy, we demonstrate that members belonging to the TRPV subfamily are expressed endogenously in the human T cell line Jurkat, in primary human T cells and in primary murine splenic T cells. We also demonstrate that TRPV1-and TRPV4-specific agonists, namely resiniferatoxin and 4a-phorbol-12,13-didecanoate, can cause Ca 2+ influx in T cells. Moreover, our results show that expression of these channels can be upregulated in T cells during concanavalin A-driven mitogenic and anti-CD3/CD28 stimulated TCR activation of T cells. By specific blocking of TRPV1 and TRPV4 channels, we found that these TRPV inhibitors may regulate mitogenic and T cell receptor mediated T cell activation and effector cytokine(s) production by suppressing tumour necrosis factor, interleukin-2 and interferon-c release. These results may have broad implications in the context of cell-mediated immunity, especially T cell responses and their regulations, neuro-immune interactions and molecular understanding of channelopathies.

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“…Trpv1 -/- [14], but recently it has been reported that B6. Trpv1 -/- do not develop MOG 35-55 peptide induced EAE suggesting some immune influence [39], despite animals being obtained from the same source and using essentially the same EAE induction technique. This further highlights the inconsistency of MOG peptide-induced EAE that can sometimes occur in C57BL/6 mice [14,39].…”

Section: Discussionmentioning

confidence: 99%

“…Whether this influenced susceptibility in GPR55 knockout mice is unknown, but must be borne in mind when considering the data. However, the differences in susceptibility reported between C57BL/6.Trpv1 are unlikely to relate to genetics as the animals were from the same source, indicating that variation in disease induction can occur [14,39]. At the time of study there were no specific, high affinity GPR55 antagonists available to confirm the influence on disease course.…”

Section: Discussionmentioning

confidence: 99%

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

et al. 2013

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Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 tm1Zim) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 Dgen) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 tm1Zim mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.

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TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

Cited by 24 publications

References 60 publications

The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T‐cell response

The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T‐cell response

Functional expression of TRPV channels in T cells and their implications in immune regulation

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

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