Transcriptome sequencing in atherosclerotic plaques identified **CCL3**, **CCL4**, and **CXCL1** as hub chemokines linked to altered immune cell infiltration.
Background
Atherosclerotic plaque (AP) is a chronic inflammatory fibrous tissue disease that can lead to severe cardiovascular and cerebrovascular obstructions. Despite its inflammatory nature, current therapeutic approaches specifically targeting inflammation in AP have largely failed, highlighting a critical gap in our understanding of the underlying pathological mechanisms. Deeper insights into the specific inflammatory factors and immune cell dynamics within these plaques are essential for developing more effective and targeted interventions. This study aimed to precisely map the inflammatory factor-related transcriptomic changes in AP to identify key mediators.
Study Design
Researchers performed RNA-sequencing (RNA-seq) on samples from 11 atherosclerotic plaque patients and 3 control individuals to analyze transcriptomic changes. Differentially Expressed Genes (DEGs) were identified using Metascape, followed by KEGG pathway enrichment analysis via the clusterProfiler package. Immune infiltration analysis was conducted using CIBERSORT to characterize the immune microenvironment. A protein-protein interaction (PPI) network was constructed using the STRING database, and central hub genes within this network were pinpointed using the CytoHubba plugin.
Results
A comprehensive analysis identified a total of 3713 differentially expressed genes (DEGs) in the atherosclerotic plaque group compared to controls, comprising 2097 up-regulated and 1616 down-regulated genes. These DEGs were predominantly enriched in immune- and inflammation-related pathways, confirming the prominent inflammatory signature of AP. > Three specific inflammation-related factors, CCL3, CCL4, and CXCL1, were identified as major hub genes within the PPI network, suggesting their critical roles in the pathological progression of AP. Immune infiltration analysis further revealed a distinct microenvironment within atherosclerotic plaques, characterized by a significant increase in M0 macrophages. Concurrently, there were notable reductions in CD8⁺ T cells, activated NK cells, and resting mast cells within the plaque tissue, indicating a profound dysregulation of the local immune landscape.
Key Findings
- 3713 DEGs identified in atherosclerotic plaques (2097 up-regulated, 1616 down-regulated).
- CCL3, CCL4, and CXCL1 identified as major hub genes in AP pathology.
- Significant increase in M0 macrophages within atherosclerotic plaque microenvironment.
- Reductions in CD8⁺ T cells, activated NK cells, and resting mast cells in AP.
DEGsprimarily enriched in immune- and inflammation-related pathways.
Why It Matters
Identifying CCL3, CCL4, and CXCL1 as central hub chemokines provides novel, specific targets for developing therapies against atherosclerosis, moving beyond broad anti-inflammatory strategies that have previously underperformed. These findings offer a mechanistic explanation for the persistent inflammation and altered immune cell composition observed in atherosclerotic plaques, particularly the detrimental accumulation of M0 macrophages. While this is a foundational preclinical study, it lays the groundwork for future drug development, potentially leading to targeted small molecule inhibitors or antibody-based interventions. The insights could ultimately inform more precise, personalized medicine approaches for managing cardiovascular disease by modulating specific chemokine pathways.
atherosclerosis
inflammation
rna-seq
chemokines
ccl3
ccl4