Exploring immune checkpoints as potential therapeutic targets in atherosclerosis

Abstract

In the past decades, the inflammatory nature of atherosclerosis has been well-recognized and despite the development of therapeutic strategies targeted at its classical risk factors such as dyslipidemia and hypertension, atherosclerosis remains a major cause of morbidity and mortality. Additional strategies targeting the chronic inflammatory pathways underlying the development of atherosclerosis are therefore required. Interactions between different immune cells result in the secretion of inflammatory mediators, such as cytokines and chemokines, and fuel atherogenesis. Immune checkpoint proteins have a critical role in facilitating immune cell interactions and play an essential role in the development of atherosclerosis. Although the therapeutic potential of these molecules is well-recognized in clinical oncology, the use of immune checkpoint modulators in atherosclerosis is still limited to experimental models. Here, we review recent insights on the role of immune checkpoint proteins in atherosclerosis. Additionally, we explore the therapeutic potential and challenges of immune checkpoint modulating strategies in cardiovascular medicine and we discuss novel therapeutic approaches to target these proteins in atherosclerosis.

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

“…The CD40-CD40L dyad is one of the best characterized immune checkpoint protein pairs and has an important role in the regulation of many immunological processes, including T cell activation, immunoglobulin isotype switching and cytokine production [8,9]. CD40 is a 43-50 kDa transmembrane protein that belongs to the tumour necrosis factor (TNF) receptor superfamily and is expressed on immune cells, e.g.…”

“…CD40 is a 43-50 kDa transmembrane protein that belongs to the tumour necrosis factor (TNF) receptor superfamily and is expressed on immune cells, e.g. B cells, dendritic cells (DC), monocytes and macrophages and nonimmune cells, including endothelial cells, vascular smooth muscle cells and fibroblasts [8,10,11]. Upon interaction with its classical ligand, CD40L (CD154), a 39-kDa transmembrane protein that is mainly expressed on activated T cells and activated platelets, trimerization of CD40 is induced [8,10,11].…”

“…One novel strategy to temper inflammation in atherosclerosis is through immune checkpoint proteins, a family consisting of co-stimulatory and co-inhibitory molecules that play a central role in the regulation of inflammation [8]. Immune checkpoint proteins are membrane proteins that are known to regulate T cell activation by providing the second signal after T cell receptor activation.…”

“…Co-stimulatory molecules boost T cell activation, whereas co-inhibitory molecules hamper cellular activation. In addition to this classical role, immune checkpoint proteins facilitate interactions between various immune cells and non-immune cells, thereby orchestrating the inflammatory response [8]. Given their central role in the regulation of inflammatory processes, modulation of immune checkpoint proteins is a promising antiinflammatory strategy for atherosclerotic CVD [8,9].…”

Prediction of the Network Pharmacology‐Based Mechanism for Attenuation of Atherosclerosis in Apolipoprotein E Knockout Mice by Panax notoginseng Saponins

“…In the present study, the expression of MMP-9 and TIMP-1 was regulated by PNS, illuminating plaque vulnerability to its products. Over the last two decades, growing evidence has revealed the main mechanism in the pathogenesis of AS, a chronic inflammatory disease [27], is inflammation [28,29]. Cytokines are known to have pivotal roles in the complex inflammatory response involved in all steps of the formation of an atherosclerotic plaque [30].…”