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TRPA1 and substance P mediate colitis in mice.
Gastroenterology 2011; 141(4):1346-58G

Abstract

BACKGROUND & AIMS

The neuropeptides calcitonin gene-related peptide (CGRP) and substance P, and calcium channels, which control their release from extrinsic sensory neurons, have important roles in experimental colitis. We investigated the mechanisms of colitis in 2 different models, the involvement of the irritant receptor transient receptor potential of the ankyrin type-1 (TRPA1), and the effects of CGRP and substance P.

METHODS

We used calcium-imaging, patch-clamp, and neuropeptide-release assays to evaluate the effects of 2,4,6-trinitrobenzene-sulfonic-acid (TNBS) and dextran-sulfate-sodium-salt on neurons. Colitis was induced in wild-type, knockout, and desensitized mice.

RESULTS

TNBS induced TRPA1-dependent release of colonic substance P and CGRP, influx of Ca2+, and sustained ionic inward currents in colonic sensory neurons and transfected HEK293t cells. Analysis of mutant forms of TRPA1 revealed that TNBS bound covalently to cysteine (and lysine) residues in the cytoplasmic N-terminus. A stable sulfinic acid transformation of the cysteine-SH group, shown by mass spectrometry, might contribute to sustained sensitization of TRPA1. Mice with colitis had increased colonic neuropeptide release, mediated by TRPA1. Endogenous products of inflammatory lipid peroxidation also induced TRPA1-dependent release of colonic neuropeptides; levels of 4-hydroxy-trans-2-nonenal increased in each model of colitis. Colitis induction by TNBS or dextran-sulfate-sodium-salt was inhibited or reduced in TRPA1-/- mice and by 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopro-pylphenyl)-acetamide, a pharmacologic inhibitor of TRPA1. Substance P had a proinflammatory effect that was dominant over CGRP, based on studies of knockout mice. Ablation of extrinsic sensory neurons prevented or attenuated TNBS-induced release of neuropeptides and both forms of colitis.

CONCLUSIONS

Neuroimmune interactions control intestinal inflammation. Activation and sensitization of TRPA1 and release of substance P induce and maintain colitis in mice.

Authors+Show Affiliations

Institute of Physiology and Pathophysiology, First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21763243

Citation

Engel, Matthias A., et al. "TRPA1 and Substance P Mediate Colitis in Mice." Gastroenterology, vol. 141, no. 4, 2011, pp. 1346-58.
Engel MA, Leffler A, Niedermirtl F, et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology. 2011;141(4):1346-58.
Engel, M. A., Leffler, A., Niedermirtl, F., Babes, A., Zimmermann, K., Filipović, M. R., ... Reeh, P. W. (2011). TRPA1 and substance P mediate colitis in mice. Gastroenterology, 141(4), pp. 1346-58. doi:10.1053/j.gastro.2011.07.002.
Engel MA, et al. TRPA1 and Substance P Mediate Colitis in Mice. Gastroenterology. 2011;141(4):1346-58. PubMed PMID: 21763243.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TRPA1 and substance P mediate colitis in mice. AU - Engel,Matthias A, AU - Leffler,Andreas, AU - Niedermirtl,Florian, AU - Babes,Alexandru, AU - Zimmermann,Katharina, AU - Filipović,Miloš R, AU - Izydorczyk,Iwona, AU - Eberhardt,Mirjam, AU - Kichko,Tatjana I, AU - Mueller-Tribbensee,Sonja M, AU - Khalil,Mohammad, AU - Siklosi,Norbert, AU - Nau,Carla, AU - Ivanović-Burmazović,Ivana, AU - Neuhuber,Winfried L, AU - Becker,Christoph, AU - Neurath,Markus F, AU - Reeh,Peter W, Y1 - 2011/07/18/ PY - 2010/12/27/received PY - 2011/06/26/revised PY - 2011/07/06/accepted PY - 2011/7/19/entrez PY - 2011/7/19/pubmed PY - 2011/12/13/medline SP - 1346 EP - 58 JF - Gastroenterology JO - Gastroenterology VL - 141 IS - 4 N2 - BACKGROUND & AIMS: The neuropeptides calcitonin gene-related peptide (CGRP) and substance P, and calcium channels, which control their release from extrinsic sensory neurons, have important roles in experimental colitis. We investigated the mechanisms of colitis in 2 different models, the involvement of the irritant receptor transient receptor potential of the ankyrin type-1 (TRPA1), and the effects of CGRP and substance P. METHODS: We used calcium-imaging, patch-clamp, and neuropeptide-release assays to evaluate the effects of 2,4,6-trinitrobenzene-sulfonic-acid (TNBS) and dextran-sulfate-sodium-salt on neurons. Colitis was induced in wild-type, knockout, and desensitized mice. RESULTS: TNBS induced TRPA1-dependent release of colonic substance P and CGRP, influx of Ca2+, and sustained ionic inward currents in colonic sensory neurons and transfected HEK293t cells. Analysis of mutant forms of TRPA1 revealed that TNBS bound covalently to cysteine (and lysine) residues in the cytoplasmic N-terminus. A stable sulfinic acid transformation of the cysteine-SH group, shown by mass spectrometry, might contribute to sustained sensitization of TRPA1. Mice with colitis had increased colonic neuropeptide release, mediated by TRPA1. Endogenous products of inflammatory lipid peroxidation also induced TRPA1-dependent release of colonic neuropeptides; levels of 4-hydroxy-trans-2-nonenal increased in each model of colitis. Colitis induction by TNBS or dextran-sulfate-sodium-salt was inhibited or reduced in TRPA1-/- mice and by 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopro-pylphenyl)-acetamide, a pharmacologic inhibitor of TRPA1. Substance P had a proinflammatory effect that was dominant over CGRP, based on studies of knockout mice. Ablation of extrinsic sensory neurons prevented or attenuated TNBS-induced release of neuropeptides and both forms of colitis. CONCLUSIONS: Neuroimmune interactions control intestinal inflammation. Activation and sensitization of TRPA1 and release of substance P induce and maintain colitis in mice. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/21763243/TRPA1_and_substance_P_mediate_colitis_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(11)00940-1 DB - PRIME DP - Unbound Medicine ER -