溶菌酶 1 炎症 CCR2+ 巨噬细胞促进肥胖诱发的心脏功能障碍

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-08-16 Epub Date: 2024-07-26 DOI:10.1161/CIRCRESAHA.124.324106
Lai Zhang, Huian Han, Andi Xu, Adwait Sathe, Siying Fu, Jiaqi Zhao, Wenhan Cai, Yaqing Yang, Jinting Liu, Hui Bai, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qing Yang, Zidun Wang, Yayun Gu, Chao Xing, Gabriele G Schiattarella, Steven Yan Cheng, Hanwen Zhang, Qi Chen
{"title":"溶菌酶 1 炎症 CCR2+ 巨噬细胞促进肥胖诱发的心脏功能障碍","authors":"Lai Zhang, Huian Han, Andi Xu, Adwait Sathe, Siying Fu, Jiaqi Zhao, Wenhan Cai, Yaqing Yang, Jinting Liu, Hui Bai, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qing Yang, Zidun Wang, Yayun Gu, Chao Xing, Gabriele G Schiattarella, Steven Yan Cheng, Hanwen Zhang, Qi Chen","doi":"10.1161/CIRCRESAHA.124.324106","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.</p><p><strong>Methods: </strong>In this study, we used single-cell RNA-sequencing analysis of Cd45<sup>+</sup>CD11b<sup>+</sup>F4/80<sup>+</sup> cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2<sup>+</sup> (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation.</p><p><strong>Results: </strong>We find that the <i>Ccr2</i> cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2<sup>+</sup>CX3CR1<sup>+</sup> macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the <i>RelA</i> promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.</p><p><strong>Conclusions: </strong>Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5000,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lysozyme 1 Inflamed CCR2<sup>+</sup> Macrophages Promote Obesity-Induced Cardiac Dysfunction.\",\"authors\":\"Lai Zhang, Huian Han, Andi Xu, Adwait Sathe, Siying Fu, Jiaqi Zhao, Wenhan Cai, Yaqing Yang, Jinting Liu, Hui Bai, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qing Yang, Zidun Wang, Yayun Gu, Chao Xing, Gabriele G Schiattarella, Steven Yan Cheng, Hanwen Zhang, Qi Chen\",\"doi\":\"10.1161/CIRCRESAHA.124.324106\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.</p><p><strong>Methods: </strong>In this study, we used single-cell RNA-sequencing analysis of Cd45<sup>+</sup>CD11b<sup>+</sup>F4/80<sup>+</sup> cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2<sup>+</sup> (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation.</p><p><strong>Results: </strong>We find that the <i>Ccr2</i> cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2<sup>+</sup>CX3CR1<sup>+</sup> macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the <i>RelA</i> promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.</p><p><strong>Conclusions: </strong>Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.</p>\",\"PeriodicalId\":10147,\"journal\":{\"name\":\"Circulation research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.5000,\"publicationDate\":\"2024-08-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCRESAHA.124.324106\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.124.324106","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

摘要

背景:巨噬细胞是肥胖相关心血管疾病的关键参与者,这些疾病以炎症和免疫改变为特征。然而,巨噬细胞在肥胖诱导的心脏炎症中发挥作用的病理生理机制尚不完全清楚。我们的研究旨在确定参与肥胖诱导的心脏功能障碍的关键巨噬细胞群,并研究导致炎症反应的分子机制:通过深入分析单个巨噬细胞RNA序列鉴定出的心脏巨噬细胞群,我们发现Ccr2群经历了从平衡维持到促炎症的功能转变。我们的数据突显了在代谢挑战下心脏功能障碍过程中巨噬细胞行为的特定变化。通过基于双重组酶的品系追踪方法诱导性消融 CCR2+CX3CR1+ 巨噬细胞,或选择性删除巨噬细胞 C-C 趋化因子受体 2(CCR2),可有效防止肥胖诱导的心脏功能障碍。在机理层面,我们证明肥胖诱导的 CCR2 表达巨噬细胞的功能转变是由 CCR2/ATF3/lysozyme1/NF-κB(核因子卡巴 B)信号传导介导的。最后,我们揭示了溶菌酶1作为转录激活剂的非经典作用,它与RelA启动子结合,驱动NF-κB信号传导,强烈促进肥胖症的炎症和心脏功能障碍:我们的研究结果表明,溶菌酶1可能是诊断肥胖引发的炎症和治疗肥胖引发的心脏病的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Lysozyme 1 Inflamed CCR2+ Macrophages Promote Obesity-Induced Cardiac Dysfunction.

Background: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.

Methods: In this study, we used single-cell RNA-sequencing analysis of Cd45+CD11b+F4/80+ cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2+ (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation.

Results: We find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.

Conclusions: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
期刊最新文献
Pneumonia Induced Rise in Glucagon Promotes Endothelial Damage and Thrombogenicity. LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases. Kindlin-2 Phase Separation in Response to Flow Controls Vascular Stability. CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury. Transformation of the Kidney into a Pathological Neuro-Immune-Endocrine Organ.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1