AUTHOR=Li Ximing , He Xinyong , Wang Junyan , Wang Dan , Cong Peiwei , Zhu Aisong , Chen Wenna 

TITLE=The Regulation of Exosome-Derived miRNA on Heterogeneity of Macrophages in Atherosclerotic Plaques

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02175

DOI=10.3389/fimmu.2020.02175

ISSN=1664-3224

ABSTRACT=Exosomes are nanosized vesicles secreted by most cells, which can deliver a variety of functional lipids, proteins, and RNAs into the target cells to participate in complex intercellular communications. Cells respond to certain physical, chemical, and biological stimuli by releasing exosomes. Exosomes are rich in small molecules of RNA, including miRNAs and mRNAs, which have been demonstrated to have certain functions in recipient cells. 
Recent studies on single-cell RNA sequences have revealed the transcription and heterogeneity of macrophages in Ldlr-/-mice with a high-fat diet. Five macrophage populations were found in the atherosclerotic plaques. It is worth noting that these subsets populations of macrophages seem to be endowed with different functions in lipid metabolism and catabolism. A total of 100 different expressed mRNAs were selected for these subsets' populations. Importantly, these macrophage populations were also present in human advanced atherosclerosis. To clarify the specific functions and the regulatory mechanism of these macrophage populations, we extracted exosome RNAs from the plasma of patients with chronic coronary artery disease (CAD) and performed RNA sequencing analysis. Compared with the healthy control, a total of 14 miRNAs were more significantly expressed in these patients. 5248 potential mRNAs were predicted by the bioinformatics platform. Next, we determined the outcome of the intersection of these predicted mRNAs with 100 mRNAs expressed in the above five macrophage populations. Based on the screening of miRNA-mRNA pairs, a co-expression network was drawn to find out the key RNAs. 3 down-regulated miRNAs and 5 up-regulated mRNAs were selected for validation by real-time RT-PCR. The results showed the expression of miR-4498 was low in plasma exosomes and Ctss, Ccr2, and Trem2 mRNA were highly expressed in PBMCs isolated from the CAD patients compared with healthy control. In order to clarify the regulatory mechanism, we established a co-culture system in vitro. Studies have shown that the uptake of exosomes from CAD patients can up-regulate the expression of Ctss, Trem2, and Ccr2 mRNA in THP-1 cells induced by LPS. 
Our findings have revealed a unique relationship between transcriptional signature and phenotypic heterogeneity of macrophage in the atherosclerotic microenvironment.