Innate Lymphoid Cells Promote Recovery of Ventricular Function After Myocardial Infarction.
cytokines
heart failure
innate lymphoid cells
interleukin-2
lymphocytes
myocardial infarction
Journal
Journal of the American College of Cardiology
ISSN: 1558-3597
Titre abrégé: J Am Coll Cardiol
Pays: United States
ID NLM: 8301365
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
14
05
2021
revised:
06
07
2021
accepted:
13
07
2021
entrez:
10
9
2021
pubmed:
11
9
2021
medline:
18
12
2021
Statut:
ppublish
Résumé
Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development. ILC2s also reside in the pericardium but their role in postischemic injury is unknown. We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS). We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine. ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.
Sections du résumé
BACKGROUND
Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development.
OBJECTIVES
ILC2s also reside in the pericardium but their role in postischemic injury is unknown.
METHODS
We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS).
RESULTS
We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine.
CONCLUSIONS
ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.
Identifiants
pubmed: 34503682
pii: S0735-1097(21)05696-5
doi: 10.1016/j.jacc.2021.07.018
pmc: PMC8434674
pii:
doi:
Substances chimiques
Interleukin-2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1127-1142Subventions
Organisme : Department of Health
ID : BRC-1215-20014
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S026193/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/10/001/27642
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/18/20/33595
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/20/23/34784
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/15/99/31865
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N028015/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 208363/Z/17/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RCAG/521
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Funding Support and Author Disclosures This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub. Dr Newland has received funding from the British Heart Foundation (PG/18/20/33595). Dr Yu has been funded by a Royal Society Newton Advanced fellowship (NA140277). The work received support from European Research Area Network on Cardiovascular Diseases Joint Transnational Call (ERA-CVD JTC) 2017-PLAQUEFIGHT). Dr Sun has been funded by the Federation Française de Cardiologie. The LILACS trial was funded by the Medical Research Council, grant number MR/N028015/1, the British Heart Foundation Cambridge Centre of Excellence (RCAG/521). Mr Cheriyan has received funding support from the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Dr Rudd has been part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, HEFCE, the EPSRC, and the Wellcome Trust. This NGS work was performed with the Genomics and Transcriptomics Core, which is funded by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_00014/5) and a Wellcome Trust Major Award (208363/Z/17/Z). All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Références
Circulation. 2016 Mar 1;133(9):826-39
pubmed: 26819373
J Immunol. 2000 May 15;164(10):4991-5
pubmed: 10799849
JACC Cardiovasc Imaging. 2015 Dec;8(12):1417-1426
pubmed: 26577262
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Front Physiol. 2014 Jun 11;5:212
pubmed: 24966838
Genes Dis. 2018 Mar 13;6(1):35-42
pubmed: 30906831
Nature. 2013 Oct 10;502(7470):245-8
pubmed: 24037376
Heart. 2016 Mar;102(5):341-8
pubmed: 26674987
Nat Commun. 2017 Jun 07;8:15781
pubmed: 28589929
Immunity. 2019 Mar 19;50(3):707-722.e6
pubmed: 30824323
Circulation. 2019 Mar 19;139(12):1530-1547
pubmed: 30586758
Front Cardiovasc Med. 2016 Oct 14;3:40
pubmed: 27790620
Immunity. 2014 Aug 21;41(2):283-95
pubmed: 25088770
Immunity. 1999 Jan;10(1):127-36
pubmed: 10023777
J Biol Chem. 2005 Nov 11;280(45):38102-7
pubmed: 16157596
J Allergy Clin Immunol. 2015 Dec;136(6):1653-1663.e7
pubmed: 26025126
Circ Res. 2014 Jun 20;115(1):55-67
pubmed: 24786398
J Exp Med. 2007 Nov 26;204(12):3037-47
pubmed: 18025128
Circulation. 2007 Aug 7;116(6):654-63
pubmed: 17646584
Nat Med. 2013 Oct;19(10):1273-80
pubmed: 24037091
J Exp Med. 2020 Feb 3;217(2):
pubmed: 31699824
JACC Basic Transl Sci. 2020 Jul 08;5(7):665-681
pubmed: 32760855
Immunity. 2010 Mar 26;32(3):426-36
pubmed: 20303297
Blood Adv. 2017 Mar 30;1(10):577-589
pubmed: 29296700
Circ Res. 2013 Sep 27;113(8):1004-12
pubmed: 23836795
Basic Res Cardiol. 2012 Jan;107(1):232
pubmed: 22189560
Nature. 2012 Jul 19;487(7407):325-9
pubmed: 22763456
J Am Soc Nephrol. 2012 Aug;23(8):1303-8
pubmed: 22677553
Science. 2006 Mar 31;311(5769):1924-7
pubmed: 16484453
BMJ Open. 2018 Sep 17;8(9):e022452
pubmed: 30224390
Circ Res. 2014 May 9;114(10):1611-22
pubmed: 24625784
Arterioscler Thromb Vasc Biol. 2020 Apr;40(4):853-864
pubmed: 32078364
Circulation. 2012 Apr 3;125(13):1652-63
pubmed: 22388323
Nat Commun. 2020 Apr 27;11(1):2049
pubmed: 32341343
Front Immunol. 2019 Mar 29;10:634
pubmed: 30984196
Blood. 2014 Dec 4;124(24):3572-6
pubmed: 25323825