The Paradigm Change of IL-33 in Vascular Biology

Abstract

In this review, we focus on the actual understanding of the role of IL-33 in vascular biology in the context of the historical development since the description of IL-33 as a member of IL-1 superfamily and the ligand for ST2 receptor in 2005. We summarize recent data on the biology, structure and signaling of this dual-function factor with both nuclear and extracellular cytokine properties. We describe cellular sources of IL-33, particularly within vascular wall, changes in its expression in different cardio-vascular conditions and mechanisms of IL-33 release. Additionally, we summarize the regulators of IL-33 expression as well as the effects of IL-33 itself in cells of the vasculature and in monocytes/macrophages in vitro combined with the consequences of IL-33 modulation in models of vascular diseases in vivo. Described in murine atherosclerosis models as well as in macrophages as an atheroprotective cytokine, extracellular IL-33 induces proinflammatory, prothrombotic and proangiogenic activation of human endothelial cells, which are processes known to be involved in the development and progression of atherosclerosis. We, therefore, discuss that IL-33 can possess both protective and harmful effects in experimental models of vascular pathologies depending on experimental conditions, type and dose of administration or method of modulation.

Keywords: ST2; atherosclerosis; interleukin-33; thrombosis; vascular.

Figure 1

The effects of IL-33 on human ECs. The release of IL-33 occurs following severe tissue damage upon cell injury, necrosis, mechanical stress or infection. When released, IL-33 binds to ST2 receptor on the cell surface as well as to circulating sST2, which negatively regulates IL-33-signalling. Upon binding to ST2 receptor, IL-33 activates several intracellular pathways, including the NF-κB-pathway. It was previously shown that IL-33 induces inflammatory activation of ECs and increases endothelial expression of IL-1, IL-6, IL-8, VCAM-1, ICAM-1, E-selectin and MCP-1. Evidence indicates that IL-33 also increases the expression and activity of u-PA, PAI-1 and TF in human ECs via ST2/NF-κB-pathway. In addition, mRNA and protein expressions of TFPI are reduced. At the same time, IL-33 induces the release of procoagulant MVs from ECs, but the mechanism for this effect remains unclear. In this manner, IL-33 activates human endothelium and promotes a proinflammatory, angiogenic and thrombotic state of human ECs. IL: interleukin; VCAM-1: vascular cell adhesion molecule-1; ICAM-1: intercellular adhesion molecule-1; E-selectin: endothelial selectin; MCP-1: monocyte chemoattractant protein-1; u-PA: urokinase-type plasminogen activator; PAI-1: plasminogen activator inhibitor type-1; TF: tissue factor; TFPI: tissue factor pathway inhibitor; MVs: microvesicles. Upwards arrows indicate upregulation, downwards arrows indicate downregulation.

Figure 2

Potential role of IL-33 in the pathogenesis of atherosclerosis. (A): IL-33 induces IL-1, IL-6, IL-8, ICAM-1, VCAM-1, E-selectin and MCP-1 in human ECs. This results in the formation of a proinflammatory environment with increased leukocyte adhesion and transmigration. Central panel: Once resident in the arterial intima, monocytes acquire morphological characteristics of macrophages, it undergoes a series of changes that lead ultimately to foam cell formation. Intimal macrophages also secrete u-PA and contribute to SMC migration and intimal thickening. Increased pericellular proteolysis results in degradation of ECM and thinning of the fibrous cap. Later in the development of an atherosclerotic lesion, macrophages, foam cells, SMCs and other cell types present in the plaque become apoptotic and contribute to the necrotic core formation. (B): IL-33-induced u-PA expression results in increased migration, tube formation and vessel sprouting of ECs. Furthermore, IL-33 and u-PA are co-expressed in ECs of microvessels within carotid plaques. Formation of microvessels can have nutritive function and stimulate the plaque growth. In addition, fragile microvessels rupture easily and intra-plaque hemorrhage contributes to the formation of an unstable plaque. Thus, by inducing u-PA expression, IL-33 could contribute to both growth and vulnerability of atherosclerotic plaque. (C): IL-33 robustly increased TF production and activity in human ECs, as well as the release of procoagulant endothelial MVs. In this manner, IL-33 could result in the formation of a prothrombotic microenvironment surrounding atherosclerotic plaque. Endothelial TF-positive MVs are also present in the necrotic core and increase the thrombogenicity of atherosclerotic plaque. Although IL-33-induced TF expression in ECs alone might not dramatically increase TF content of the entire atherosclerotic plaque, accumulation of TF in ECs can result in apoptosis and contribute to endothelial denudation and to the exposure of the highly prothrombotic core of the atherosclerotic plaque. (D): Increased inflammation, pericellular proteolysis, angiogenesis and increased TF production could contribute to growth and destabilization of atherosclerotic plaque, resulting eventually in plaque rupture and thrombosis. IL: interleukin; VCAM-1: vascular cell adhesion molecule-1; ICAM-1: intercellular adhesion molecule-1; E-selectin: endothelial selectin; MCP-1: monocyte chemoattractant protein-1; u-PA: urokinase-type plasminogen activator; TF: tissue factor; MVs: microvesicles.