title: Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.
abstract: 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.
  
  
  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.
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Xiaoxiang
authors: X
authors: Yan
authors: Takashi
authors: T
authors: Shichita
authors: Yoshinori
authors: Y
authors: Katsumata
authors: Tomohiro
authors: T
authors: Matsuhashi
authors: Hideyuki
authors: H
authors: Ito
authors: Kentaro
authors: K
authors: Ito
authors: Atsushi
authors: A
authors: Anzai
authors: Jin
authors: J
authors: Endo
authors: Yuichi
authors: Y
authors: Tamura
authors: Kensuke
authors: K
authors: Kimura
authors: Jun
authors: J
authors: Fujita
authors: Ken
authors: K
authors: Shinmura
authors: Weifeng
authors: W
authors: Shen
authors: Akihiko
authors: A
authors: Yoshimura
authors: Keiichi
authors: K
authors: Fukuda
authors: Motoaki
authors: M
authors: Sano
mesh_terms: D000818:Animals; D017209:Apoptosis; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000276:immunology*; D032383:Myocytes, Cardiac / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D020257:Ventricular Remodeling / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23
keywords: heart failure; immune system; inflammation; myocardial infarction; remodeling