Lysozyme 1 Inflamed CCR2 <sup>+</sup> Macrophages Promote Obesity-Induced Cardiac Dysfunction-Reference-Cited by-同舟云学术

Lysozyme 1 Inflamed CCR2 ⁺ Macrophages Promote Obesity-Induced Cardiac Dysfunction

Published:2024-08-16 Issue:5 Volume:135 Page:596-613
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circulation Research

Author:

Zhang Lai¹²³^ORCID,Han Huian¹²^ORCID,Xu Andi⁴^ORCID,Sathe Adwait⁵^ORCID,Fu Siying¹²,Zhao Jiaqi¹²,Cai Wenhan¹²^ORCID,Yang Yaqing¹²^ORCID,Liu Jinting¹²,Bai Hui¹²,Ben Jingjing¹²^ORCID,Zhu Xudong¹²,Li Xiaoyu¹²,Yang Qing¹²,Wang Zidun⁶^ORCID,Gu Yayun⁷,Xing Chao⁵⁸⁹^ORCID,Schiattarella Gabriele G.¹⁰¹¹¹²^ORCID,Cheng Steven Yan²^ORCID,Zhang Hanwen¹²^ORCID,Chen Qi¹²^ORCID

Affiliation:

1. Department of Pathophysiology (L.Z., H.H., S.F., J.Z., W.C., Y.Y., J.L., H.B., J.B., X.Z., X.L., Q.Y., H.Z., Q.C.), Nanjing Medical University, Jiangsu, China.

2. Key Laboratory of Jiangsu Province on Targeted Intervention of Cardiovascular Diseases (L.Z., H.H., S.F., J.Z., W.C., Y.Y., J.L., H.B., J.B., X.Z., X.L., Q.Y., S.Y.C., H.Z., Q.C.), Nanjing Medical University, Jiangsu, China.

3. Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University, China (L.Z.).

4. Department of Pathology, Nanjing Drum Tower Hospital, China (A.X.).

5. Eugene McDermott Center for Human Growth and Development (A.S., C.X.), University of Texas Southwestern Medical Center, Dallas.

6. Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, China (Z.W.).

7. State Key Laboratory of Reproductive Medicine (Y.G.), Nanjing Medical University, Jiangsu, China.

8. Department of Bioinformatics (C.X.), University of Texas Southwestern Medical Center, Dallas.

9. Department of Population and Data Sciences (C.X.), University of Texas Southwestern Medical Center, Dallas.

10. Max Rubner Center for Cardiovascular Metabolic Renal Research, Deutsches Herzzentrum der Charité, Charité - Universitätsmedizin Berlin, Germany (G.G.S.).

11. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany (G.G.S.).

12. Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (G.G.S.).

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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