Inhibition of Interleukin-21 prolongs the survival through the promotion of wound healing after myocardial infarction. (October 2021)

• Record Type: Journal Article
• Authors: Kubota, Akihiko; Suto, Akira; Suga, Kensuke; Iwata, Arifumi; Tanaka, Shigeru; Suzuki, Kotaro; Kobayashi, Yoshio; Nakajima, Hiroshi
• Is Part Of: Journal of molecular and cellular cardiology. Volume 159(2021)
• Page Start: 48
• Page End: 61
• Publication Date: 2021-10
• Subjects: IL-21 -- Myocardial infarction -- Wound healing -- Myocardial inflammation; AWT anterior wall thickness -- Auto autofluorescence -- BW body weight -- DC dendritic cell -- FDR false discovery rate -- FS fractional shortening -- γc common cytokine receptor γ chain -- GO Gene Ontology -- IL interleukin -- IL-21R interleukin-21 receptor α chain -- IL-21RFc interleukin-21 receptor /human IgG Fc-chimera protein -- LAD left anterior descending coronary -- LV left ventricular -- LVEDD left ventricular end-diastolic diameter -- LVESD left ventricular end-systolic diameter -- Ly6Chi macrophage Ly6Chigh macrophage -- Ly6Clo macrophage Ly6Clow macrophage -- MerTK myeloid-epithelial-reproductive receptor tyrosine kinase -- MI myocardial infarction -- MMP matrix metalloproteinase -- PMA phorbol 12-myristate 13-acetate -- PWT posterior wall thickness -- qPCR quantitative real-time reverse transcriptase-polymerase chain reaction -- RNA-seq RNA-sequencing -- 7-AAD 7-Amino-Actinomycin D -- SMA smooth muscle actin -- WT wild-type -- WAD weighted average difference; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.06.006
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Ly6C low macrophages promote scar formation and prevent early infarct expansion after myocardial infarction (MI). Although CD4 + T cells influence the regulation of Ly6C low macrophages after MI, the mechanism remains largely unknown. Based on the hypothesis that some molecule(s) secreted by CD4 + T cells act on Ly6C low macrophages, we searched for candidate molecules by focusing on cytokine receptors expressed on Ly6C low macrophages. Comparing the transcriptome between Ly6C high macrophages and Ly6C low macrophages harvested from the infarcted heart, we found that Ly6C low macrophages highly expressed the receptor for interleukin (IL)-21, a pleiotropic cytokine which is produced by several types of CD4 + T cells, compared with Ly6C high macrophages. Indeed, CD4 + T cells harvested from the infarcted heart produce IL-21 upon stimulation. Importantly, the survival rate and cardiac function after MI were significantly improved in IL-21-deficient (il21 −/− ) mice compared with those in wild-type (WT) mice. Transcriptome analysis of infarcted heart tissue from WT mice and il21 −/− mice at 5 days after MI demonstrated that inflammation is persistent in WT mice compared with il21 −/− mice. Consistent with the transcriptome analysis, the number of neutrophils and matrix metalloproteinase (MMP)-9 expression were significantly decreased, whereas the number of Ly6C low macrophages and MMP-12 expression were significantly increased in il21 −/− mice. In addition, collagen deposition and the number of myofibroblasts in the infarcted area were significantly increased in il21 −/− mice. Consistently, IL-21 enhanced the apoptosis of Ly6C low macrophages. Finally, administration of neutralizing IL-21 receptor Fc protein increased the number of Ly6C low macrophages in the infarcted heart and improved the survival and cardiac function after MI. Thus, IL-21 decreases the survival after MI, possibly through the delay of wound healing by inducing the apoptosis of Ly6C low macrophages. Graphical abstract: Unlabelled Image Highlights: IL-21 receptor was highly expressed in Ly6C low macrophages in the infarcted heart. IL-21 deficiency improves cardiac function and increases survival rate after MI. IL-21 deficiency increases Ly6C low macrophage numbers in the infarcted heart. IL-21 deficiency suppresses inflammation and promotes wound healing. Neutralization of IL-21 also increases survival rate after MI in wild-type mice.