Chemokine Ligands and Receptors Regulate Macrophage Polarization in Atherosclerosis: A Comprehensive Database Mining Study

Abstract

Background

Atherosclerosis is a systemic disease involving multiple blood vessels and a major cause of cardiovascular disease. Current treatment methods (eg, statins) for atherosclerosis can reduce the risk of cardiovascular diseases effectively, but they are insufficient to completely reverse existing atherosclerosis. Macrophages play a central role in development of atherosclerosis. Chemokines, the main mediators of macrophage chemotaxis, are important in immune and inflammatory responses. The effects of chemokines on mechanisms involved in atherosclerosis are unknown. This study preliminarily investigated these effects and mechanisms via bioinformatics methods.

Methods

In this study, data on chemokine ligands and receptors were obtained by mining public databases (the National Center of Biotechnology Information-Gene Expression Omnibus [NCBI-GEO] database, ArrayExpress database, and single-cell RNA sequencing [scRNA-seq] database), and an extensive literature search was performed. The expression levels of chemokines in mouse tissues were analyzed via Metascape software for signalling pathway enrichment, scRNA-seq data for chemokine expression in atherosclerotic plaque progression and regression, and GEO2R data for chemokine expression during macrophage polarization. Ingenuity Pathway Analysis (IPA) software was used to analyze regulatory factors such as transcription factors and microRNAs that are significantly differentially expressed upstream of chemokines in macrophage polarization. Finally, a model of the chemokine regulation of atherosclerosis was established on the basis of these results.

Results

There are 5 main findings: (1) In atherosclerosis, chemokines are regulated by transcription factors and microRNAs. (2) The transcription factor STAT1 promotes the polarization of dormant (M0) macrophages into classically activated (M1) macrophages and alternative activated (M2) macrophages by regulating chemokines. The transcription factors STAT1, IRF7 and IRF1 regulate the polarization of M0 macrophages into M2a and M2b macrophages via different chemokines. For example, some transcription factors promote M1 polarization of M0 macrophages through CCL4, but M2 macrophage polarization is regulated via CCL19, CCL5 and CCR7. (3) Transcription factors can promote and inhibit, whereas miRNAs can only inhibit atherosclerosis. (4) CCL4 existed in all 5 different chemokine-regulated macrophage models, whereas CXCL3 only existed in the M2b macrophage transcriptional regulation model, indicating that CXCL3 may promote the M2b type macrophages polarization of M0 macrophages. (5) CCL5 and CCR7 can promote the M2a macrophages and M2b macrophages polarization of M0 macrophages.

Conclusions

Atherosclerosis can be treated by regulating chemokines and regulating the polarization of macrophages. The chemokines CCL4, CCL5, CCL8, CCL19, CXCL3, CXCL10, CXCL13, and CCR7 may play key roles in the progression and regression of atherosclerosis.