Atherosclerosis is a major human killer and non-resolving inflammation is a prime suspect

Abstract

The resolution of inflammation (or inflammation-resolution) is an active and highly coordinated process. Inflammation-resolution is governed by several endogenous factors, and specialized pro-resolving mediators (SPMs) are one such class of molecules that have robust biological function. Non-resolving inflammation is associated with a variety of human diseases, including atherosclerosis. Moreover, non-resolving inflammation is a hallmark of ageing, an inevitable process associated with increased risk for cardiovascular disease. Uncovering mechanisms as to why inflammation-resolution is impaired in ageing and in disease and identifying useful biomarkers for non-resolving inflammation are unmet needs. Recent work has pointed to a critical role for balanced ratios of SPMs and pro-inflammatory lipids (i.e. leucotrienes and/or specific prostaglandins) as a key determinant of timely inflammation resolution. This review will focus on the accumulating findings that support the role of non-resolving inflammation and imbalanced pro-resolving and pro-inflammatory mediators in atherosclerosis. We aim to provide insight as to why these imbalances occur, the importance of ageing in disease progression, and how haematopoietic function impacts inflammation-resolution and atherosclerosis. We highlight open questions regarding therapeutic strategies and mechanisms of disease to provide a framework for future studies that aim to tackle this important human disease.

Keywords: Ageing; Atherosclerosis; Immunology; Inflammation; hematopoiesis.

Figure 1

Schematic of SPM generation and their actions via specific GPCRs on select cellular targets. Precursor fatty acids, including arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or n-3 docosapentaenoic acid (_n-3DPA), are biosynthesized into several families of SPMs by the action of enzymes including 5-LOX, 15-LOX, and COX-2. The receptors for many SPMs have been identified, as shown, but many remain to be elucidated. SPMs also have distinct cellular targets, though more work is needed to examine cell-specific expression of receptors under different conditions and in different tissues.

Figure 2

Proposed scheme for SPM:LT/PG imbalances in advanced atherosclerotic plaques. Macrophages are major cellular players in atherosclerosis and can biosynthesize PG, LTs, and SPMs. How a macrophage ‘chooses’ to produce a SPM or an LT for example, may in part be due to localization of 5-LOX. Phosphorylated and nuclear 5-LOX drives LT synthesis, while non-nuclear synthesis promotes the formation of SPMs like lipoxins. Pro-inflammatory factors and oxidative stress drive nuclear 5-LOX in macrophages which may be one of many mechanisms associated with an imbalance in SPM:LT in advanced atherosclerotic plaques.