Data Mining of IFNgamma-induced macrophage and Atherosclerotic Plaque Transcriptomes predicts a macrophage-specific role of STAT1 in human atherosclerosis [BMDM]

Atherosclerosis is a chronic inflammatory disease of the blood vessels, characterized by atherosclerotic lesions. Early vascular injury initiates excessive inflammatory and immune responses, communicated by blood leukocytes and cells from the vasculature. Key factors contributing to early stages of atherosclerosis and plaque development include the pro-inflammatory cytokine IFNγ, which is vital for both innate and adaptive immunity and is also expressed at high levels in atherosclerotic lesions. Recent discoveries provide novel evidence to suggest that IFNγ-activated STAT1 orchestrates a platform of cell-type common and specific inflammatory responses in Vascular Smooth Muscle Cells (VSMC) and macrophages (MΦ) that are instrumental in the onset and progression of atherosclerotic plaque formation. Therefore, we compared genome-wide transcriptional responses of mouse VSMCs and bone marrow-derived macrophages (BMDMs) in time-dependent IFNγ response using RNA-seq. We identified genes upregulated both in a common and cell-type-specific manner. Next, comparative analysis with RNAseq data from aortic plaques from HFD-treated ApoEKO mice identified 225 differentially expressed genes with a BMDM-specific character. These included many known IFNγ target genes containing putative GAS and ISRE sites in their promoters. Likewise, using a scRNAseq data set obtained from human coronary atherosclerotic plaques, identified 98 pro-inflammatory and pro-atherogenic genes that were characterized as BMDM-specific and exclusively expressed in foamy, inflammatory, monocytes and tissue-resident BMDM subtypes. Finally, we identified a 25 BMDM-specific gene subset commonly expressed in mouse and human plaques, over-representing STAT1-binding sites and predominantly associated with Leukocyte Chemotaxis and Migration. These results provide strong evidence for a BMDM-specific role of STAT1 in coronary artery plaque development and identify a BMDM-specific STAT1-dependent pro-inflammatory gene signature that could serve to monitor and diagnose plaque progression in human atherosclerosis.