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Inhibition of fibroblast IL-6 production by ACKR4 deletion alleviates cardiac remodeling after myocardial infarction

Fibrotic scarring is tightly linked to the development of heart failure in patients with post-myocardial infarction (MI). Atypical chemokine receptor 4 (ACKR4) can eliminate chemokines, such as C–C chemokine ligand 21 (CCL21), which is independently associated with heart failure mortality. However,...

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Published in:Biochemical and biophysical research communications 2021-04, Vol.547, p.139-147
Main Authors: Zhang, Min, Zhou, Ting, Liu, Meilin, Xia, Ni, Gu, Muyang, Tang, Tingting, Nie, Shaofang, Zhu, Zhengfeng, Lv, Bingjie, Jiao, Jiao, Yang, Xiangping, Cheng, Xiang
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cited_by cdi_FETCH-LOGICAL-c356t-59866a766c4c8f8aca26dc82faff2a37774a5ec484de0bc058181c2f64341b053
cites cdi_FETCH-LOGICAL-c356t-59866a766c4c8f8aca26dc82faff2a37774a5ec484de0bc058181c2f64341b053
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container_title Biochemical and biophysical research communications
container_volume 547
creator Zhang, Min
Zhou, Ting
Liu, Meilin
Xia, Ni
Gu, Muyang
Tang, Tingting
Nie, Shaofang
Zhu, Zhengfeng
Lv, Bingjie
Jiao, Jiao
Yang, Xiangping
Cheng, Xiang
description Fibrotic scarring is tightly linked to the development of heart failure in patients with post-myocardial infarction (MI). Atypical chemokine receptor 4 (ACKR4) can eliminate chemokines, such as C–C chemokine ligand 21 (CCL21), which is independently associated with heart failure mortality. However, the role of ACKR4 in the heart during MI is unrevealed. This study aimed to determine whether ACKR4 modulates cardiac remodeling following MI and to illuminate the potential molecular mechanisms. The expression of ACKR4 was upregulated in the border/infarct area, and ACKR4 was predominantly expressed in cardiac fibroblasts (CFs). Knockout of ACKR4 protected against adverse ventricular remodeling in mice post-MI. These protective effects of ACKR4 deficiency were independent of dendritic cell immune response but could be attributed to downregulated CF-derived IL-6, affecting CF proliferation and endothelial cell (EC) functions, which consequently inhibited cardiac fibrosis. ACKR4 promoted IL-6 generation and proliferation of CFs. Besides, ACKR4 induced endothelial-to-mesenchymal transition (EndMT) in ECs through IL-6 paracrine effect. The p38 MAPK/NF-κB signaling pathway was involved in ACKR4 facilitated IL-6 generation. Moreover, ACKR4 overexpression in vivo via AAV9 carrying a periostin promoter aggravated heart functional impairment post-MI, which was abolished by IL-6 neutralizing antibody. Therefore, our study established a novel link between ACKR4 and IL-6 post-MI, indicating that ACKR4 may be a novel therapeutic target to ameliorate cardiac remodeling. •ACKR4 expression is upregulated in infarcted heart and exclusively detected in CFs.•ACKR4 deletion alleviates cardiac remodeling after MI.•The cardioprotective effect induced by ACKR4 deletion is DCs-trafficking independent.•Knockout of ACKR4 reduces proliferation, IL-6 generation of CFs in vitro.•Overexpression of ACKR4 aggravates cardiac dysfunction after MI via IL-6 in vivo.
doi_str_mv 10.1016/j.bbrc.2021.02.013
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Atypical chemokine receptor 4 (ACKR4) can eliminate chemokines, such as C–C chemokine ligand 21 (CCL21), which is independently associated with heart failure mortality. However, the role of ACKR4 in the heart during MI is unrevealed. This study aimed to determine whether ACKR4 modulates cardiac remodeling following MI and to illuminate the potential molecular mechanisms. The expression of ACKR4 was upregulated in the border/infarct area, and ACKR4 was predominantly expressed in cardiac fibroblasts (CFs). Knockout of ACKR4 protected against adverse ventricular remodeling in mice post-MI. These protective effects of ACKR4 deficiency were independent of dendritic cell immune response but could be attributed to downregulated CF-derived IL-6, affecting CF proliferation and endothelial cell (EC) functions, which consequently inhibited cardiac fibrosis. ACKR4 promoted IL-6 generation and proliferation of CFs. Besides, ACKR4 induced endothelial-to-mesenchymal transition (EndMT) in ECs through IL-6 paracrine effect. The p38 MAPK/NF-κB signaling pathway was involved in ACKR4 facilitated IL-6 generation. Moreover, ACKR4 overexpression in vivo via AAV9 carrying a periostin promoter aggravated heart functional impairment post-MI, which was abolished by IL-6 neutralizing antibody. 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Besides, ACKR4 induced endothelial-to-mesenchymal transition (EndMT) in ECs through IL-6 paracrine effect. The p38 MAPK/NF-κB signaling pathway was involved in ACKR4 facilitated IL-6 generation. Moreover, ACKR4 overexpression in vivo via AAV9 carrying a periostin promoter aggravated heart functional impairment post-MI, which was abolished by IL-6 neutralizing antibody. 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subjects ACKR4
Cardiac fibrosis
Fibroblasts
IL-6
Myocardial infarction
title Inhibition of fibroblast IL-6 production by ACKR4 deletion alleviates cardiac remodeling after myocardial infarction
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