The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1

Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung; Jong, Petrus R. de; Kim, Peter; Han, Tiffany; Yu, Timothy; To, Keith; Takahashi, Naoki; Boland, Brigid S.; Chang, John T.; Ho, Samuel B.; Herdman, Scott; Corr, Maripat; Franco, Alessandra; Sharma, Sonia; Dong, Hui; Akopian, Armen N.; Raz, Eyal

doi:10.1136/gutjnl-2015-310710

Cited by 106 publications

(130 citation statements)

References 47 publications

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“…A current study [46] demonstrated that TPRA1-/-CD4+ T cells have increased T-cell receptor-induced Ca 2+ influx, activation profile and subsequent differentiation into Th1-effector cells. The study suggests a protective role of TRPA1 in T-cellmediated colitis as well as activation by GA of a non-selective cation current in lymphocytes that could contribute to a decrease in IL-α production.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. Methods: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1β levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 μg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 μg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1β levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. Results: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1β or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na⁺ current (I_Na), with a negative shift in the inactivation curve of I_Na and reduced the amplitude of APs along with decreased firing of APs. Conclusion: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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“…Our results suggest that TRPA1 plays an important role relevant for T cell activation, likely by different endogenous factors. In a recent report, the functional expression of TRPA1 in murine and human CD4 + T cells has been shown to regulate T cell activation and pro-inflammatory responses [20]. However, the previous reports have suggested a proinflammatory role of TRPA1 towards immune activation and inflammation [21].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recently it has been reported that CD4 + T cell-associated TRPA1 may regulate inflammation in experimental colitis model in mice [20]. However, evidence for any such functional requirement of TRPA1 in T cell responses, in vitro, remains scanty.…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Ankyrin1 channel is endogenously expressed in T cells and regulates immune functions

Rk²,

Tiwari³

et al. 2019

Preprint

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Transient Receptor Potential channel subfamily A member 1 (TRPA1) is a non selective cationic channel, identified initially as a cold sensory receptor. TRPA1 responds to diverse exogenous and endogenous stimuli associated with pain and inflammation. However, the role of TRPA1 towards T cell responses remains scanty. In this work, we explored the endogenous expression of TRPA1 in T cells. By RT-PCR we confirmed the expression of TRPA1 in T cell at RNA level. Using confocal microscopy as well as flow cytometry, we demonstrated that TRPA1 is endogenously expressed in primary murine splenic T cells as well as in primary human T cells. The endogenous expression of TRPA1 is confirmed by using another antibody. TRPA1 was primarily located at the cell surface.TRPA1-specific activator namely AITC increases intracellular Ca 2+ -levels while two different inhibitors namely A-967079 as well as HC-030031 reduce intracellular Ca 2+ -levels in T cells. Such Ca 2+ -influx can also be influenced by chelation of intracellular Ca 2+ as well as extracellular Ca 2+ .TRPA1 expression was found to be increased during αCD3/αCD28 (TCR) or ConA driven stimulation in T cells. TRPA1-specific inhibitor treatment prevented induction of CD25, CD69 in ConA/TCR stimulated T cells and secretion of cytokines like TNF, IFN- and IL-2 suggesting that endogenous activity of TRPA1 may be involved in T cell activation. Collectively these results may have implication in T cell-mediated responses and possible role of TRPA1 in immunological disorders.

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“…Icilin is described as a superagonist of TRPM8, but can also reportedly activate TRPA1 at higher concentrations (31,32). As TRPA1 is functionally expressed in lymphocyte populations and plays a key inhibitory role in CD4 + T-cell responses (33), we sought to determine whether the effect of icilin on T-cell proliferation was dependent on either TRPM8 or TRPA1. Consistent with icilin exerting its protective role in EAE in a TRPM8independent fashion (Fig.…”

Section: Icilin Induces a Dose-dependent Reduction In Cd4 + T-cell Prmentioning

confidence: 99%

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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The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1

Cited by 106 publications

References 47 publications

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Transient Receptor Potential Ankyrin1 channel is endogenously expressed in T cells and regulates immune functions

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

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