The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1.
Transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-1 (TRPV1) are calcium (Ca2+)-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 ofTrpa1gene deletion in two models of experimental colitis (ie, interleukin-10 knockout and T-cell-adoptive transfer models). We performed electrophysiological and Ca2+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 ofTrpa1-/-CD4+ T cells. We also analysedTRPA1andTRPV1gene 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 thatTrpa1-/-CD4+ T cells have increased T-cell receptor-induced Ca2+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 ofTRPA1andTRPV1gene 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.
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Samuel
S
Bertin
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.|Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan.
Yukari
Y
Aoki-Nonaka
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Jihyung
J
Lee
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Petrus R
PR
de Jong
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Peter
P
Kim
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Tiffany
T
Han
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Timothy
T
Yu
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Keith
K
To
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.|Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan.
Naoki
N
Takahashi
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California, USA.|Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.
Brigid S
BS
Boland
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California, USA.|Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.
John T
JT
Chang
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California, USA.|Division of Gastroenterology, Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA.
Samuel B
SB
Ho
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Scott
S
Herdman
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Maripat
M
Corr
Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
Alessandra
A
Franco
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Sonia
S
Sharma
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Hui
H
Dong
Department of Endodontics, UTHSCSA, San Antonio, Texas, USA.
Armen N
AN
Akopian
Division of Rheumatology, Allergy & Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Eyal
E
Raz
D000818:Animals; D001706:Biopsy / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology; D051379:Mice; D065840:Protective Factors; D013223:Statistics as Topic; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism
D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse
CALCIUM; EXPERIMENTAL COLITIS; IBD; ION CHANNELS; T LYMPHOCYTES