Abstract
Atherosclerosis is a chronic autoimmune inflammatory disease that can cause coronary artery disease, stroke, peripheral artery disease, depending on which arteries are affected. At the beginning of atherosclerosis plasma lipoproteins accumulate in the sub-endothelial space. In response, monocytes migrate from the circulation through the endothelium into the intima where they differentiate into macrophages. These early events trigger a complex immune response that eventually involves many cellular subtypes of both innate and adaptive immunity. The Notch signaling pathway is an evolutionary conserved cell signaling system that mediates cell-to-cell communication. Recent studies have revealed that Notch modulate atherosclerosis by controlling macrophages polarization into M1 or M2 subtypes. Furthermore, it is known that Notch signaling controls differentiation and activity of T-helper and cytotoxic T-cells in inflammatory diseases. In this review, we will discuss the role of Notch in modulating immunity in the context of atherosclerosis and whether targeting Notch may represent a therapeutic strategy.
Highlights
Atherosclerosis is widely recognized as the most common cause of coronary artery disease, periphery artery disease, and stroke and the most relevant player in mortality and morbidity in the entire world
Small molecules inhibiting γsecretase (GSI, γ-secretase inhibitors), the enzyme necessary for the activation of Notch, have been originally developed because γ-secretase is involved in a β-amyloid polypeptide, found in brains of Alzheimer’s disease patients [11]. During these past 20 years GSIs with different specificity and modality of action and other Notch blocking agents have been developed and are currently being investigated in clinical trials for those cancers driven by dysregulation of this pathway [12, 13]. In this Review, we will describe the role of Notch in the modulation of immune responses during the different phases of atherosclerosis and discuss available evidence suggesting that the targeting of this pathway may represent a novel therapeutic strategy for this disease
Resident CCR2macrophages inhibit pro-inflammatory leukocyte recruitment protecting from adverse remodeling after myocardial infarction (MI) [64, 65]. These findings indicate that Notch signaling in monocytes and vascular macrophages promotes inflammation by facilitating a pro-inflammatory M1 phenotype at the expense of the anti-inflammatory M2 subtype
Summary
Francesco Vieceli Dalla Sega 1*, Francesca Fortini 1, Giorgio Aquila 2, Gianluca Campo 1,3, Mauro Vaccarezza 4 and Paola Rizzo 1,5,6. Atherosclerosis is a chronic autoimmune inflammatory disease that can cause coronary artery disease, stroke, peripheral artery disease, depending on which arteries are affected. Monocytes migrate from the circulation through the endothelium into the intima where they differentiate into macrophages. These early events trigger a complex immune response that eventually involves many cellular subtypes of both innate and adaptive immunity. Recent studies have revealed that Notch modulate atherosclerosis by controlling macrophages polarization into M1 or M2 subtypes. It is known that Notch signaling controls differentiation and activity of T-helper and cytotoxic T-cells in inflammatory diseases. We will discuss the role of Notch in modulating immunity in the context of atherosclerosis and whether targeting Notch may represent a therapeutic strategy
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