Cargando…
Deleterious Effect of the IL-23/IL-17A Axis and γδT Cells on Left Ventricular Remodeling After Myocardial Infarction
BACKGROUND: Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. METHODS AND RESULTS: We created a large MI by permanent li...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541626/ https://www.ncbi.nlm.nih.gov/pubmed/23316306 http://dx.doi.org/10.1161/JAHA.112.004408 |
_version_ | 1782255393393606656 |
---|---|
author | Yan, Xiaoxiang Shichita, Takashi Katsumata, Yoshinori Matsuhashi, Tomohiro Ito, Hideyuki Ito, Kentaro Anzai, Atsushi Endo, Jin Tamura, Yuichi Kimura, Kensuke Fujita, Jun Shinmura, Ken Shen, Weifeng Yoshimura, Akihiko Fukuda, Keiichi Sano, Motoaki |
author_facet | Yan, Xiaoxiang Shichita, Takashi Katsumata, Yoshinori Matsuhashi, Tomohiro Ito, Hideyuki Ito, Kentaro Anzai, Atsushi Endo, Jin Tamura, Yuichi Kimura, Kensuke Fujita, Jun Shinmura, Ken Shen, Weifeng Yoshimura, Akihiko Fukuda, Keiichi Sano, Motoaki |
author_sort | Yan, Xiaoxiang |
collection | PubMed |
description | BACKGROUND: Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. METHODS AND RESULTS: We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)–23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas >90% of IL-17A-producing T cells in infarcted heart were CD4(−) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. CONCLUSIONS: The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy. |
format | Online Article Text |
id | pubmed-3541626 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-35416262013-01-11 Deleterious Effect of the IL-23/IL-17A Axis and γδT Cells on Left Ventricular Remodeling After Myocardial Infarction Yan, Xiaoxiang Shichita, Takashi Katsumata, Yoshinori Matsuhashi, Tomohiro Ito, Hideyuki Ito, Kentaro Anzai, Atsushi Endo, Jin Tamura, Yuichi Kimura, Kensuke Fujita, Jun Shinmura, Ken Shen, Weifeng Yoshimura, Akihiko Fukuda, Keiichi Sano, Motoaki J Am Heart Assoc Original Research BACKGROUND: Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. METHODS AND RESULTS: We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)–23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas >90% of IL-17A-producing T cells in infarcted heart were CD4(−) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. CONCLUSIONS: The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy. Blackwell Publishing Ltd 2012-10-25 /pmc/articles/PMC3541626/ /pubmed/23316306 http://dx.doi.org/10.1161/JAHA.112.004408 Text en © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. http://creativecommons.org/licenses/by/2.5/ This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Yan, Xiaoxiang Shichita, Takashi Katsumata, Yoshinori Matsuhashi, Tomohiro Ito, Hideyuki Ito, Kentaro Anzai, Atsushi Endo, Jin Tamura, Yuichi Kimura, Kensuke Fujita, Jun Shinmura, Ken Shen, Weifeng Yoshimura, Akihiko Fukuda, Keiichi Sano, Motoaki Deleterious Effect of the IL-23/IL-17A Axis and γδT Cells on Left Ventricular Remodeling After Myocardial Infarction |
title | Deleterious Effect of the IL-23/IL-17A Axis and
γδT Cells on Left Ventricular Remodeling After Myocardial
Infarction |
title_full | Deleterious Effect of the IL-23/IL-17A Axis and
γδT Cells on Left Ventricular Remodeling After Myocardial
Infarction |
title_fullStr | Deleterious Effect of the IL-23/IL-17A Axis and
γδT Cells on Left Ventricular Remodeling After Myocardial
Infarction |
title_full_unstemmed | Deleterious Effect of the IL-23/IL-17A Axis and
γδT Cells on Left Ventricular Remodeling After Myocardial
Infarction |
title_short | Deleterious Effect of the IL-23/IL-17A Axis and
γδT Cells on Left Ventricular Remodeling After Myocardial
Infarction |
title_sort | deleterious effect of the il-23/il-17a axis and
γδt cells on left ventricular remodeling after myocardial
infarction |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541626/ https://www.ncbi.nlm.nih.gov/pubmed/23316306 http://dx.doi.org/10.1161/JAHA.112.004408 |
work_keys_str_mv | AT yanxiaoxiang deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT shichitatakashi deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT katsumatayoshinori deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT matsuhashitomohiro deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT itohideyuki deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT itokentaro deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT anzaiatsushi deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT endojin deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT tamurayuichi deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT kimurakensuke deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT fujitajun deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT shinmuraken deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT shenweifeng deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT yoshimuraakihiko deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT fukudakeiichi deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction AT sanomotoaki deleteriouseffectoftheil23il17aaxisandgdtcellsonleftventricularremodelingaftermyocardialinfarction |