Notch Signaling Regulates Immune Responses in Atherosclerosis

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.

COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm?

“…Among the proposed mechanisms of myocardial and lung injury caused by SARS-CoV-2, there is a "cytokine storm" triggered by an imbalanced response by type 1 and type 2 T helper (Th) cells [53]. The Notch pathway plays a major role during the differentiation and the activity of innate and adaptive immune cells [30,49]. Dll4/Notch signalling is an important inducer of M1 macrophage polarisation and experiments in vitro and in vivo have shown that inhibition of the Notch by GSI or by anti-Dll4 antibodies leads to a dampening of the inflammation [49].…”

“…The Notch pathway plays a major role during the differentiation and the activity of innate and adaptive immune cells [30,49]. Dll4/Notch signalling is an important inducer of M1 macrophage polarisation and experiments in vitro and in vivo have shown that inhibition of the Notch by GSI or by anti-Dll4 antibodies leads to a dampening of the inflammation [49]. In macrophages, Notch1 directly binds to interleukin (IL)-6 promoter in response to interferon (IFN)-γ and positively regulates IL-6 production [52].…”

“…It is important to underline that IL-6, in turn, increases the expression of the Notch ligand Dll1, thus amplifying the Notch signalling and establishing a positive feedback loop that promotes the further production of IL-6 [21]. In Th cells, Notch signalling triggered by Dll1,4 ligands promotes the production of inflammatory Th1/Th17 cytokines, whereas Jagged1 suppresses IL-6-induced Th17 activation [49] (Fig. 2).…”

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease

“…To date, the molecular mechanisms underlying these pleiotropic effects of ticagrelor have not been elucidated, but there is evidence suggesting that they are related to inhibition of the equilibrative nucleoside transporter-1 (ENT1) leading to increased circulating levels of adenosine and cyclic adenosine monophosphate (cAMP) [9,10]. Adenosine, by binding adenosine receptors (ARs), regulates biological processes involved in CAD and COPD progression including oxidative stress and inflammatory responses [11], and functions of monocytes, neutrophils, CD4 T-helper cells, and CD8 cytotoxic T-cells, all implicated in CAD [12,13]. Specifically, in human monocytes, adenosine reduces inflammation through the inhibition of the expression of adhesion molecules, such as intercellular adhesion molecule 1 (ICAM1) [14].…”

“…Dysregulation of the Notch signaling, a major regulator of cardiovascular homeostasis and of innate and adaptive immune response, has been observed in cardiovascular diseases [13,29]. Specifically, altered levels of Notch ligands JAGGED-1 (JAG1) and Delta-like 4 (DLL4) have been linked to the progression of atherosclerosis [30,31].…”