TRPA1 and substance P mediate colitis in mice

Matthias A. Engel; Andreas Leffler; Florian Niedermirtl; Alexandru Babes; Katharina Zimmermann; Milo R. Filipovi; Iwona Izydorczyk; Mirjam Eberhardt; Tatjana I. Kichko; Sonja M. Muellertribbensee; Mohammad Khalil; Norbert Siklosi; Carla Nau; Ivana Ivanoviburmazovi; Winfried L. Neuhuber; Christoph Becker; Markus F. Neurath; Peter W. Reeh

doi:10.1053/j.gastro.2011.07.002

TRPA1 and substance P mediate colitis in mice

Matthias A. Engel, Andreas Leffler, Florian Niedermirtl, Alexandru Babes, Katharina Zimmermann, Milo R. Filipovi, Iwona Izydorczyk, Mirjam Eberhardt, Tatjana I. Kichko, Sonja M. Muellertribbensee, Mohammad Khalil, Norbert Siklosi, Carla Nau, Ivana Ivanoviburmazovi, Winfried L. Neuhuber, Christoph Becker, Markus F. Neurath, Peter W. Reeh^*

^*Corresponding author for this work

Department of Anesthesiology and Intensive Care Medicine

195 Citations (Scopus)

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.

Original language	English
Journal	Gastroenterology
Volume	141
Issue number	4
Pages (from-to)	1346-1358
Number of pages	13
ISSN	0016-5085
DOIs	https://doi.org/10.1053/j.gastro.2011.07.002
Publication status	Published - 10.2011

Funding

Funding Peter Reeh and Matthias Engel were supported by the Federal Ministry of Education and Res. (BMBF0315449C); Matthias Engel received additional support from the Marohn-Stiftung of the Friedrich-Alexander-Universität Erlangen-Nürnberg; Alexandru Babes was supported by grant PN2 Idei 164/2007 from the Romanian Government and by a visiting scientist grant from the Humboldt Foundation ; and the chemical analytic work by Miloš Filipović and Ivana Ivanović–Burmazović was supported by the Deutsche Forschungsgemeinschaft.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1053/j.gastro.2011.07.002

Cite this

Engel, M. A., Leffler, A., Niedermirtl, F., Babes, A., Zimmermann, K., Filipovi, M. R., Izydorczyk, I., Eberhardt, M., Kichko, T. I., Muellertribbensee, S. M., Khalil, M., Siklosi, N., Nau, C., Ivanoviburmazovi, I., Neuhuber, W. L., Becker, C., Neurath, M. F., & Reeh, P. W. (2011). TRPA1 and substance P mediate colitis in mice. Gastroenterology, 141(4), 1346-1358. https://doi.org/10.1053/j.gastro.2011.07.002

@article{40a403d2b82842fd8d4a97fff2fe2d3b,

title = "TRPA1 and substance P mediate colitis in mice",

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.",

author = "Engel, \{Matthias A.\} and Andreas Leffler and Florian Niedermirtl and Alexandru Babes and Katharina Zimmermann and Filipovi, \{Milo R.\} and Iwona Izydorczyk and Mirjam Eberhardt and Kichko, \{Tatjana I.\} and Muellertribbensee, \{Sonja M.\} and Mohammad Khalil and Norbert Siklosi and Carla Nau and Ivana Ivanoviburmazovi and Neuhuber, \{Winfried L.\} and Christoph Becker and Neurath, \{Markus F.\} and Reeh, \{Peter W.\}",

note = "Funding Information: Funding Peter Reeh and Matthias Engel were supported by the Federal Ministry of Education and Res. (BMBF0315449C); Matthias Engel received additional support from the Marohn-Stiftung of the Friedrich-Alexander-Universit{\"a}t Erlangen-N{\"u}rnberg; Alexandru Babes was supported by grant PN2 Idei 164/2007 from the Romanian Government and by a visiting scientist grant from the Humboldt Foundation ; and the chemical analytic work by Milo{\v s} Filipovi{\'c} and Ivana Ivanovi{\'c}–Burmazovi{\'c} was supported by the Deutsche Forschungsgemeinschaft. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

year = "2011",

month = oct,

doi = "10.1053/j.gastro.2011.07.002",

language = "English",

volume = "141",

pages = "1346--1358",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "4",

}

Engel, MA, Leffler, A, Niedermirtl, F, Babes, A, Zimmermann, K, Filipovi, MR, Izydorczyk, I, Eberhardt, M, Kichko, TI, Muellertribbensee, SM, Khalil, M, Siklosi, N, Nau, C, Ivanoviburmazovi, I, Neuhuber, WL, Becker, C, Neurath, MF & Reeh, PW 2011, 'TRPA1 and substance P mediate colitis in mice', Gastroenterology, vol. 141, no. 4, pp. 1346-1358. https://doi.org/10.1053/j.gastro.2011.07.002

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 - Filipovi, Milo R.

AU - Izydorczyk, Iwona

AU - Eberhardt, Mirjam

AU - Kichko, Tatjana I.

AU - Muellertribbensee, Sonja M.

AU - Khalil, Mohammad

AU - Siklosi, Norbert

AU - Nau, Carla

AU - Ivanoviburmazovi, Ivana

AU - Neuhuber, Winfried L.

AU - Becker, Christoph

AU - Neurath, Markus F.

AU - Reeh, Peter W.

N1 - Funding Information: Funding Peter Reeh and Matthias Engel were supported by the Federal Ministry of Education and Res. (BMBF0315449C); Matthias Engel received additional support from the Marohn-Stiftung of the Friedrich-Alexander-Universität Erlangen-Nürnberg; Alexandru Babes was supported by grant PN2 Idei 164/2007 from the Romanian Government and by a visiting scientist grant from the Humboldt Foundation ; and the chemical analytic work by Miloš Filipović and Ivana Ivanović–Burmazović was supported by the Deutsche Forschungsgemeinschaft. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2011/10

Y1 - 2011/10

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.

AB - 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.

UR - https://www.scopus.com/pages/publications/80053600154

U2 - 10.1053/j.gastro.2011.07.002

DO - 10.1053/j.gastro.2011.07.002

M3 - Journal articles

AN - SCOPUS:80053600154

SN - 0016-5085

VL - 141

SP - 1346

EP - 1358

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

TRPA1 and substance P mediate colitis in mice

Abstract

Funding

UN SDGs

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CRU 130, Subproject: Interaction of nociceptor-specific membrane proteins with anesthetics and analgesics

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TRPA1 and substance P mediate colitis in mice

Abstract

Funding

UN SDGs

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Projects

CRU 130, Subproject: Interaction of nociceptor-specific membrane proteins with anesthetics and analgesics

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