Unveiling macrophage diversity in myocardial ischemia-reperfusion injury: identification of a distinct lipid-associated macrophage subset

• Published in: Frontiers in immunology 2024-02, Vol.15, p.1335333
• Main Authors: Jiang, Ying, Yu, Wenpeng, Hu, Tie, Peng, Hanzhi, Hu, Fajia, Yuan, Yong, Liu, Xufeng, Lai, Songqing, Zhou, Jianliang, Dong, Xiao
• Format: Article
• Language: English
• Subjects: Animals; bioinformatics; Genes, Reporter; Humans; Immunology; lipid-associated macrophage; Lipids; macrophage heterogeneity; Macrophages; Membrane Glycoproteins; Mice; Myocardial Ischemia; myocardial ischemia-reperfusion injury; Myocardial Reperfusion Injury - genetics; Receptors, Immunologic; single-cell sequencing
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1335333

Macrophages play a crucial and dichotomous role cardiac repair following myocardial ischemia-reperfusion, as they can both facilitate tissue healing and contribute to injury. This duality is intricately linked to environmental factors, and the identification of macrophage subtypes within the context of myocardial ischemia-reperfusion injury (MIRI) may offer insights for the development of more precise intervention strategies. Specific marker genes were used to identify macrophage subtypes in GSE227088 (mouse single-cell RNA sequencing dataset). Genome Set Enrichment Analysis (GSEA) was further employed to validate the identified LAM subtypes. Trajectory analysis and single-cell regulatory network inference were executed using the R packages Monocle2 and SCENIC, respectively. The conservation of LAM was verified using human ischemic cardiomyopathy heart failure samples from the GSE145154 (human single-cell RNA sequencing dataset). Fluorescent homologous double-labeling experiments were performed to determine the spatial localization of LAM-tagged gene expression in the MIRI mouse model. In this study, single-cell RNA sequencing (scRNA-seq) was employed to investigate the cellular landscape in ischemia-reperfusion injury (IRI). Macrophage subtypes, including a novel Lipid-Associated Macrophage (LAM) subtype characterized by high expression of Spp1, Trem2, and other genes, were identified. Enrichment and Progeny pathway analyses highlighted the distinctive functional role of the SPP1+ LAM subtype, particularly in lipid metabolism and the regulation of the MAPK pathway. Pseudotime analysis revealed the dynamic differentiation of macrophage subtypes during IRI, with the activation of pro-inflammatory pathways in specific clusters. Transcription factor analysis using SCENIC identified key regulators associated with macrophage differentiation. Furthermore, validation in human samples confirmed the presence of SPP1+ LAM. Co-staining experiments provided definitive evidence of LAM marker expression in the infarct zone. These findings shed light on the role of LAM in IRI and its potential as a therapeutic target. In conclusion, the study identifies SPP1+ LAM macrophages in ischemia-reperfusion injury and highlights their potential in cardiac remodeling.