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

• Published in: Gut Vol. 66; no. 9; p. 1584
• Main Authors: Bertin, Samuel, Aoki-Nonaka, Yukari, Lee, Jihyung, de Jong, Petrus R, 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
• Format: Journal Article
• Language: English
• Published: England 01-09-2017
• Subjects: Animals; Biopsy - methods; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Colon - metabolism; Colon - pathology; Disease Models, Animal; Gene Expression - physiology; Humans; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; Mice; Protective Factors; Statistics as Topic; Transient Receptor Potential Channels - genetics; Transient Receptor Potential Channels - metabolism; TRPA1 Cation Channel; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; IBD; ION CHANNELS; EXPERIMENTAL COLITIS; T LYMPHOCYTES; CALCIUM
• ISSN: 1468-3288
• DOI: 10.1136/gutjnl-2015-310710

Transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-1 (TRPV1) are calcium (Ca
)-permeable ion channels mostly known as pain receptors in sensory neurons. However, growing evidence suggests their crucial involvement in the pathogenesis of IBD. We explored the possible contribution of TRPA1 and TRPV1 to T-cell-mediated colitis.
We evaluated the role of
gene deletion in two models of experimental colitis (ie, interleukin-10 knockout and T-cell-adoptive transfer models). We performed electrophysiological and Ca
imaging studies to analyse TRPA1 and TRPV1 functions in CD4+ T cells. We used genetic and pharmacological approaches to evaluate TRPV1 contribution to the phenotype of
CD4+ T cells. We also analysed
and
gene expression and TRPA1
TRPV1
T cell infiltration in colonic biopsies from patients with IBD.
We identified a protective role for TRPA1 in T-cell-mediated colitis. We demonstrated the functional expression of TRPA1 on the plasma membrane of CD4+ T cells and identified that
CD4+ T cells have increased T-cell receptor-induced Ca
influx, activation profile and differentiation into Th1-effector cells. This phenotype was abrogated upon genetic deletion or pharmacological inhibition of the TRPV1 channel in mouse and human CD4+ T cells. Finally, we found differential regulation of
and
gene expression as well as increased infiltration of TRPA1
TRPV1
T cells in the colon of patients with IBD.
Our study indicates that TRPA1 inhibits TRPV1 channel activity in CD4+ T cells, and consequently restrains CD4+ T-cell activation and colitogenic responses. These findings may therefore have therapeutic implications for human IBD.