Lysozyme 1 inflamed CCR2(+) macrophages promote obesity-induced cardiac dysfunction

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Item Type:	Article
Title:	Lysozyme 1 inflamed CCR2(+) macrophages promote obesity-induced cardiac dysfunction
Creators Name:	Zhang, L., Han, H., Xu, A., Sathe, A., Fu, S., Zhao, J., Cai, W., Yang, Y., Liu, J., Bai, H., Ben, J., Zhu, X., Li, X., Yang, Q., Wang, Z., Gu, Y., Xing, C., Schiattarella, G.G., Cheng, S.Y., Zhang, H. and Chen, Q.
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 AND RESULTS: Though analyzing in-depth cardiac macrophage clusters identified by single macrophage RNA-sequencing, 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 by a dual recombinase-based lineage-tracing approach or selective deletion of macrophage C-C chemokine receptor 2 (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/ATF3/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:	Cardiovascular Diseases, Inflammation, Macrophages, Muramidase, RNA, Animals, Mice
Source:	Circulation Research
ISSN:	0009-7330
Publisher:	American Heart Association
Volume:	135
Number:	5
Page Range:	596-613
Date:	16 August 2024
Official Publication:	https://doi.org/10.1161/CIRCRESAHA.124.324106
PubMed:	View item in PubMed

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