three-dimensional-imaging-of-aortic-tissues-in-atherosclerosis

Three-Dimensional Imaging of Aortic Tissues in Atherosclerosis

Recent research has advanced the understanding of atherosclerosis as a transmural chronic inflammatory disease involving all three layers of the arterial ...

the first affiliated hospital of Sun Yat-sen University

Ludwig-Maximilians-University

Atherosclerotic plaques form in the inner layer of arteries triggering heart attacks and strokes. Although T cells have been detected in atherosclerosis, tolerance dysfunction as a disease driver remains unexplored. Here we examine tolerance checkpoints in atherosclerotic plaques, artery tertiary lymphoid organs and lymph nodes in mice burdened by advanced atherosclerosis, via single-cell RNA sequencing paired with T cell antigen receptor sequencing. Complex patterns of deteriorating peripheral T cell tolerance were observed being most pronounced in plaques followed by artery tertiary lymphoid organs, lymph nodes and blood. Affected checkpoints included clonal expansion of CD4, CD8 and regulatory T cells; aberrant tolerance-regulating transcripts of clonally expanded T cells; T cell exhaustion; T-TH T cell conversion; and dysfunctional antigen presentation. Moreover, single-cell RNA-sequencing profiles of human plaques revealed that the CD8 T cell tolerance dysfunction observed in mouse plaques was shared in human coronary and carotid artery plaques. Thus, our data support the concept of atherosclerosis as a bona fide T cell autoimmune disease targeting the arterial wall.

Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis.

Three systemic biological systems, i.e., the nervous, the immune, and the cardiovascular systems, form a mutually responsive and forward-acting tissue network to regulate acute and chronic cardiovascular function in health and disease. Two sub-circuits within the cardiovascular system have been described, the artery brain circuit (ABC) and the heart brain circuit (HBC), forming a large cardiovascular brain circuit (CBC). Likewise, the nervous system consists of the peripheral nervous system and the central nervous system with their functional distinct sensory and effector arms. Moreover, the immune system with its constituents, i.e., the innate and the adaptive immune systems, interact with the CBC and the nervous system at multiple levels. As understanding the structure and inner workings of the CBC gains momentum, it becomes evident that further research into the CBC may lead to unprecedented classes of therapies to treat cardiovascular diseases as multiple new biologically active molecules are being discovered that likely affect cardiovascular disease progression. Here, we weigh the merits of integrating these recent observations in cardiovascular neurobiology into previous views of cardiovascular disease pathogeneses. These considerations lead us to propose the Neuroimmune Cardiovascular Circuit Hypothesis.

Ting Sun

Division of Vascular Surgery,
Institute of Precision Medicine

the first affiliated hospital of Sun Yat-sen University

Three-Dimensional Imaging of Aortic Tissues in Atherosclerosis

Ting Sun

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Vascular Surgery,Institute of Precision Medicine

the first affiliated hospital of Sun Yat-sen University

Three-Dimensional Imaging of Aortic Tissues in Atherosclerosis

Division of Vascular Surgery,
Institute of Precision Medicine