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Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways
Enteric glial cells (EGCs) are components of the intestinal epithelial barrier essential for regulating the enteric nervous system. Clostridium difficile is the most common cause of antibiotic-associated colitis, toxin B (TcdB) being the major virulence factor, due to its ability to breach the intes...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368562/ https://www.ncbi.nlm.nih.gov/pubmed/28349972 http://dx.doi.org/10.1038/srep45569 |
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author | Macchioni, Lara Davidescu, Magdalena Fettucciari, Katia Petricciuolo, Maya Gatticchi, Leonardo Gioè, Davide Villanacci, Vincenzo Bellini, Massimo Marconi, Pierfrancesco Roberti, Rita Bassotti, Gabrio Corazzi, Lanfranco |
author_facet | Macchioni, Lara Davidescu, Magdalena Fettucciari, Katia Petricciuolo, Maya Gatticchi, Leonardo Gioè, Davide Villanacci, Vincenzo Bellini, Massimo Marconi, Pierfrancesco Roberti, Rita Bassotti, Gabrio Corazzi, Lanfranco |
author_sort | Macchioni, Lara |
collection | PubMed |
description | Enteric glial cells (EGCs) are components of the intestinal epithelial barrier essential for regulating the enteric nervous system. Clostridium difficile is the most common cause of antibiotic-associated colitis, toxin B (TcdB) being the major virulence factor, due to its ability to breach the intestinal epithelial barrier and to act on other cell types. Here we investigated TcdB effects on EGCs and the activated molecular mechanisms. Already at 2 hours, TcdB triggered ROS formation originating from NADPH-oxidase, as demonstrated by their reduction in the presence of the NADPH-oxidase inhibitor ML171. Although EGCs mitochondria support almost completely the cellular ATP need, TcdB exerted weak effects on EGCs in terms of ATP and mitochondrial functionality, mitochondrial ROS production occurring as a late event. ROS activated the JNK signalling and overexpression of the proapoptotic Bim not followed by cytochrome c or AIF release to activate the downstream apoptotic cascade. EGCs underwent DNA fragmentation through activation of the ROS/JNK/caspase-3 axis, evidenced by the ability of ML171, N-acetylcysteine, and the JNK inhibitor SP600125 to inhibit caspase-3 or to contrast apoptosis. Therefore, TcdB aggressiveness towards EGCs is mainly restricted to the cytosolic compartment, which represents a peculiar feature, since TcdB primarily influences mitochondria in other cellular types. |
format | Online Article Text |
id | pubmed-5368562 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53685622017-03-30 Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways Macchioni, Lara Davidescu, Magdalena Fettucciari, Katia Petricciuolo, Maya Gatticchi, Leonardo Gioè, Davide Villanacci, Vincenzo Bellini, Massimo Marconi, Pierfrancesco Roberti, Rita Bassotti, Gabrio Corazzi, Lanfranco Sci Rep Article Enteric glial cells (EGCs) are components of the intestinal epithelial barrier essential for regulating the enteric nervous system. Clostridium difficile is the most common cause of antibiotic-associated colitis, toxin B (TcdB) being the major virulence factor, due to its ability to breach the intestinal epithelial barrier and to act on other cell types. Here we investigated TcdB effects on EGCs and the activated molecular mechanisms. Already at 2 hours, TcdB triggered ROS formation originating from NADPH-oxidase, as demonstrated by their reduction in the presence of the NADPH-oxidase inhibitor ML171. Although EGCs mitochondria support almost completely the cellular ATP need, TcdB exerted weak effects on EGCs in terms of ATP and mitochondrial functionality, mitochondrial ROS production occurring as a late event. ROS activated the JNK signalling and overexpression of the proapoptotic Bim not followed by cytochrome c or AIF release to activate the downstream apoptotic cascade. EGCs underwent DNA fragmentation through activation of the ROS/JNK/caspase-3 axis, evidenced by the ability of ML171, N-acetylcysteine, and the JNK inhibitor SP600125 to inhibit caspase-3 or to contrast apoptosis. Therefore, TcdB aggressiveness towards EGCs is mainly restricted to the cytosolic compartment, which represents a peculiar feature, since TcdB primarily influences mitochondria in other cellular types. Nature Publishing Group 2017-03-28 /pmc/articles/PMC5368562/ /pubmed/28349972 http://dx.doi.org/10.1038/srep45569 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Macchioni, Lara Davidescu, Magdalena Fettucciari, Katia Petricciuolo, Maya Gatticchi, Leonardo Gioè, Davide Villanacci, Vincenzo Bellini, Massimo Marconi, Pierfrancesco Roberti, Rita Bassotti, Gabrio Corazzi, Lanfranco Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways |
title | Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways |
title_full | Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways |
title_fullStr | Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways |
title_full_unstemmed | Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways |
title_short | Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways |
title_sort | enteric glial cells counteract clostridium difficile toxin b through a nadph oxidase/ros/jnk/caspase-3 axis, without involving mitochondrial pathways |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368562/ https://www.ncbi.nlm.nih.gov/pubmed/28349972 http://dx.doi.org/10.1038/srep45569 |
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