Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis

Abstract

The development of new immunotherapies to treat the inflammatory mechanisms that sustain atherosclerotic cardiovascular disease (ASCVD) is urgently needed. Herein, we present a path to drug repurposing to identify immunotherapies for ASCVD. The integration of time-of-flight mass cytometry and RNA sequencing identified unique inflammatory signatures in peripheral blood mononuclear cells stimulated with ASCVD plasma. By comparing these inflammatory signatures to large-scale gene expression data from the LINCS L1000 dataset, we identified drugs that could reverse this inflammatory response. Ex vivo screens, using human samples, showed that saracatinib—a phase 2a-ready SRC and ABL inhibitor—reversed the inflammatory responses induced by ASCVD plasma. In Apoe−/− mice, saracatinib reduced atherosclerosis progression by reprogramming reparative macrophages. In a rabbit model of advanced atherosclerosis, saracatinib reduced plaque inflammation measured by [18F]fluorodeoxyglucose positron emission tomography–magnetic resonance imaging. Here we show a systems immunology-driven drug repurposing with a preclinical validation strategy to aid the development of cardiovascular immunotherapies.

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis

“…Functionally, we observed that 4-PBA significantly reduced the expression of ICAM-1 and CCL5 in oxLDL-treated cells (Figure 4E-F). Of note, CCL5 was recently implicated via a comprehensive bioinformatics study as the most relevant inflammatory mediator underlying human atherosclerosis 43 . Collectively, our data reveal that 4-PBA can mitigate the pro-inflammatory memory of monocytes through the attenuation of TRAM-mediated subcellular inflammatory stress.…”

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

“…Recently, the JAK inhibitor tofacitinib was reported to decrease inflammatory flare-ups in a cohort of patients with FOP [ 131 ]. Saracatinib, which has shown anti-inflammatory activity in atherosclerosis [ 132 ], is being investigated as a possible therapy for FOP [ 133 ]. Imatinib, another kinase inhibitor with anti-fibrotic and anti-inflammatory activity [ 134 , 135 , 136 ], has also been described for use in severe cases of FOP [ 137 , 138 ].…”

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

“…Atherosclerosis is a chronic inflammatory disease induced by interactions between endothelial cells, smooth muscle cells, various kinds of circulating blood cells ( e . g ., platelets, neutrophils, and monocytes), the immune system, and the peripheral nervous system 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ; these interactions lead to altered vascular cell function and the development of life-threatening atherosclerotic plaques 14 . Initially, endothelial dysfunction allows low-density lipoprotein cholesterol particles (LDL-C) to infiltrate into the vascular neointima, where they are trapped and retained by atherogenic proteoglycans with modified (hyper-elongated) glycosaminoglycan chains 15 , 16 .…”