Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Xiaoxiang Yan, Takashi Shichita, Yoshinori Katsumata, Tomohiro Matsuhashi, Hideyuki Ito, Kentaro Ito, Atsushi Anzai, Jin Endo, Yuichi Tamura, Kensuke Kimura, Jun Fujita, Ken Shinmura, Weifeng Shen, Akihiko Yoshimura, Keiichi Fukuda, Motoaki Sano

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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. 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. 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.

Original languageEnglish
JournalJournal of the American Heart Association
Volume1
Issue number5
DOIs
Publication statusPublished - 2012 Oct
Externally publishedYes

Fingerprint

Interleukin-23
Ventricular Remodeling
Interleukin-17
Myocardial Infarction
T-Lymphocytes
Macrophages
Lysosphingolipid Receptors
Neutrophil Infiltration
Toll-Like Receptors
Dilated Cardiomyopathy
Interleukin-1
Cardiac Myocytes
Ligation
Dilatation
Cell Survival
Coronary Vessels
Myocardium
Neutrophils
Fibrosis
Heart Failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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.

In: Journal of the American Heart Association, Vol. 1, No. 5, 10.2012.

Research output: Contribution to journalArticle

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. In: Journal of the American Heart Association. 2012 ; Vol. 1, No. 5.
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abstract = "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. 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. 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.",
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AU - Yan, Xiaoxiang

AU - Shichita, Takashi

AU - Katsumata, Yoshinori

AU - Matsuhashi, Tomohiro

AU - Ito, Hideyuki

AU - Ito, Kentaro

AU - Anzai, Atsushi

AU - Endo, Jin

AU - Tamura, Yuichi

AU - Kimura, Kensuke

AU - Fujita, Jun

AU - Shinmura, Ken

AU - Shen, Weifeng

AU - Yoshimura, Akihiko

AU - Fukuda, Keiichi

AU - Sano, Motoaki

PY - 2012/10

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N2 - 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. 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. 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.

AB - 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. 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. 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.

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