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

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

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

Circ Res. 2024 Aug 16;135(5):596-613. doi: 10.1161/CIRCRESAHA.124.324106. Epub 2024 Jul 26.

Authors

Lai Zhang^#^{1

2

3}, Huian Han^#^{1

2}, Andi Xu^#⁴, Adwait Sathe^#⁵, Siying Fu^{1

2}, Jiaqi Zhao^{1

2}, Wenhan Cai^{1

2}, Yaqing Yang^{1

2}, Jinting Liu^{1

2}, Hui Bai^{1

2}, Jingjing Ben^{1

2}, Xudong Zhu^{1

2}, Xiaoyu Li^{1

2}, Qing Yang^{1

2}, Zidun Wang⁶, Yayun Gu⁷, Chao Xing^{5

8

9}, Gabriele G Schiattarella^{10

11

12}, Steven Yan Cheng², Hanwen Zhang^{1

2}, Qi Chen^{1

2}

Affiliations

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.).

^# Contributed equally.

PMID: 39056179
DOI: 10.1161/CIRCRESAHA.124.324106

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.

Keywords: cardiomyopathies; cardiovascular diseases; inflammation; macrophages; obesity.

MeSH terms

Animals
Heart Diseases / etiology
Heart Diseases / genetics
Heart Diseases / metabolism
Inflammation / genetics
Inflammation / metabolism
Macrophages* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muramidase* / genetics
Muramidase* / metabolism
Obesity* / complications
Obesity* / metabolism
Receptors, CCR2* / genetics
Receptors, CCR2* / metabolism
Signal Transduction

Substances

Receptors, CCR2
Muramidase
Ccr2 protein, mouse
lysozyme M, mouse