Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and plaque formation in arterial vessel walls. Atherosclerotic plaques narrow the arterial lumen to increase the risk of heart attacks, ischemic stroke and peripheral vascular disease, which are major and worldwide health and economic burdens. Macrophage accumulation within plaques is characteristic of all stages of atherosclerosis and their presence is a potential marker of disease activity and plaque stability. Macrophages engulf lipids and modified lipoproteins to form foam cells that express pro-inflammatory and chemotactic effector molecules, stress inducing factors and reactive oxygen species. They control plaque stability and rupture through secretion of metalloproteinases and extracellular matrix degradation. Although macrophages can worsen disease by propagating inflammation, they can stabilize atherosclerotic plaques through tissue remodeling, promoting the formation of a fibrous cap, clearing apoptotic cells to prevent necrotic core formation and through vascular repair. In atherosclerosis, macrophages respond to dyslipidaemia, cytokines, dying cells, metabolic factors, lipids, physical stimuli and epigenetic factors and exhibit heterogeneity in their activation depending on the stimuli they receive. Understanding these signals and the pathways driving macrophage function within developing and established plaques and how they can be pharmacologically modulated, represents a strategy for the prevention and treatment of atherosclerosis. This review focusses on the current understanding of factors controlling macrophage heterogeneity and function in atherosclerosis. Particular attention is given to the macrophage intracellular signaling pathways and transcription factors activated by biochemical and biophysical stimuli within plaques, and how they are integrated to regulate plaque formation and stability.
Many dietary plants possess high levels of 18-carbon containing lipids from both omega-6 and omega-3 unsaturated fatty acids (e.g., linoleic and alpha-linolenic acid, respectively). These dietary lipids can be metabolized to lipid mediators collectively termed octadecanoids, which can in turn interact with immune cells (e.g., macrophages, eosinophils) to exert a number of potent biological effects. These octadecanoid lipid mediators have been little studied and represent an exciting new area of lipid biochemistry. For further information, see the review in this issue by Quaranta and colleagues (pages 1569–1582). Cover image credit: Emmanuelle Chevallier.
The intracellular signaling pathways governing macrophage activation and function in human atherosclerosis
Heather M. Wilson; The intracellular signaling pathways governing macrophage activation and function in human atherosclerosis. Biochem Soc Trans 16 December 2022; 50 (6): 1673–1682. doi: https://doi.org/10.1042/BST20220441
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