The role of IL-1β in aortic aneurysm

Highlights

• This article mainly reviews the role of IL-1 β in aortic aneurysms, and summarizes the effects of metabolism and related pathways on IL-1 and aortic aneurysms.

• IL-1 β antagonists have been shown to be drug targets for alleviate aortic aneurysms.

• Inflammation is an important factor leading to cardiovascular disease. Inhibition of IL-1 β can effectively control a series of diseases caused by inflammation.

Abstract

Interleukin-1β (IL-1β) is a vital cytokine that plays an important role in regulating immune responses to infectious challenges and sterile insults. In addition, two endogenous inhibitors of functional receptor binding, IL-1 receptor antagonist (IL-1Ra), complete the family. To gain biological activity, IL-1β requires processing by the protease caspase-1 and activation of inflammasomes. Numerous clinical association studies and experimental approaches have implicated members of the IL-1 family, their receptors, or components of the processing machinery in the underlying processes of cardiovascular diseases. Here, we summarize the current state of knowledge regarding the pro-inflammatory and disease-modulating role of the IL-1 family in aneurysm. We discuss clinical evidence, signalling pathway, and mechanism of action and last, lend a perspective on currently developing therapeutic strategies involving IL-1β in aneurysm.

Introduction

Aortic aneurysm (AA) is defined as a progressive dilation of the artery, with round (saccular) or tube-shaped (fusiform) enlargements. AA is a significant cause of mortality in developed countries. Major risk factors for AA formation include hypertension, smoking, atherosclerosis and hypercholesterolemia, and there is a significantly higher incidence and mortality in males than in females [1], [2], [3]. Hereditary diseases associated with aortic dissection/aneurysm include Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) [4]. Despite this confusion, two themes appear common in all forms of atherosclerosis and aneurysmal disease: (1) inflammation and (2) altered extracellular matrix metabolism. Indeed, these two situations commonly coexist [4]. They have no clinical treatment other than trans-arterial endovascular therapies with stent grafts or high-risk surgery when the conditions of patients are favourable to this option [5], [6]. Thus, medical therapies that could slow aneurysm progression and prevent the need for surgery are needed [7]. Presently, there are no specific medical therapies to treat or slow the progression of AA, largely because of an incomplete understanding of AA pathogenesis.

Among potential targets of therapy, IL-1β has attracted the most attention because of its crucial involvement in inflammatory diseases. The major sources of IL-1β secretion are macrophages and monocytes, dendritic cells (DC), B lymphocytes, neutrophils, and natural killer (NK) cells as well as non-immune cells such as keratinocytes [8]. Both IL-1α and IL-1β protein are encoded by different genes, and there are similar downstream biological characteristics via IL-1R.

However, differences exist in terms of their cellular source, maturation requirements, and release, which affect their impact on inflammation. IL-1β is not present in healthy individuals, and IL-1β mRNA requires an additional signal for synthesis. The stimulus can be a microbial product, but cytokines such as IL-18, TNFα, IL-1α or IL-1β itself induce IL-1β [9]. In contrast with IL-1α, pro–IL-1β, the IL-1β precursor, is not biologically active but rather requires proteolytic processing by caspase-1, resulting in the secretion of the active IL-1β cytokine. Caspase-1, the predominant IL-1 processing protease, is abundantly present in haematopoietic cells as a proenzyme, and it requires activation by the inflammasome. However, mature IL-1β can also be produced independent of caspase-1, especially in the context of local inflammation [10].

The local activation of IL-1β is central in mediating the pro-inflammatory response resulting in activation of secondary inflammatory mediators, including IL-6. In turn, IL-6 acts systemically to elicit the acute phase response with hepatic production of acute phase proteins, such as whole C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor [11]. Therefore, IL-1β plays a crucial role in inflammation-related diseases, especially cardiovascular disease [12] (see Fig. 1).

Clinical studies have demonstrated that IL-1β protein levels in human AA are approximately 20-fold higher than in normal aortas [13]. Imbalance of pathway regulation, disturbance of matrix metabolism and impairment of vascular function are accompanied by the expression of pro-inflammatory cytokine IL-1β. In turn, IL-1β increases the production of the chemokine (C-C motif) ligand 2 (CCL2). IL-1β is a potent pro-inflammatory cytokine produced primarily by macrophages that have pivotal effects on vascular disease. It causes upregulation of adhesion molecules on endothelial cells, which recruits immune cells [14]. The leukocytes are recruited in and around the aortic wall, and the consequent inflammatory response aggravates AA formation [4].

Mice with loss of Smad4 function can be used as the model of aortic aneurysm. Smad4 (−/−) smooth muscle cells overexpress pro-inflammatory cytokine IL-1β while IL-1β in turn increases the production of monocyte-macrophage chemoattractant (MCP-1), and the subsequent inflammatory response aggravates the formation of an aortic aneurysm. Other studies have shown that IL-1β or IL-1R gene deletion is associated with thoracic aortic dilatation and significantly reduced aortic structural protection. Mice with IL-1β or IL-1R deletion show less macrophage staining and lower levels of inflammatory cytokines and matrix metalloproteinase-9. At present, many pharmacological drugs target IL-1β and IL-1 receptors. Studies have shown that anakinra, a commercially available IL-1 receptor antagonist, can prevent the formation and progression of experimental thoracic and abdominal aortic aneurysms [4], [15], [13].