Dysregulated Resolution of Inflammation in Atherosclerosis: Mechanistic Insights and Therapeutic Opportunities.

Abstract

Atherosclerosis is a chronic inflammatory disease of medium- and large-sized arteries and the underlying cause of most myocardial infarctions and strokes. It develops when circulating lipoproteins accumulate within the arterial intima, triggering recruitment of monocytes, neutrophils, and other immune cells that initiate and sustain vascular inflammation. Macrophages ingest modified lipids and become foam cells, while ongoing inflammatory signalling promotes cell death, extracellular matrix remodelling, and progressive plaque growth. In early lesions, macrophages efficiently remove apoptotic cells through efferocytosis, a process that prevents secondary necrosis and promotes anti-inflammatory and tissue repair pathways. However, in advanced plaques, this clearance pathway becomes defective, leading to the accumulation of apoptotic and necrotic debris, expansion of the necrotic core, and weakening of the fibrous cap-features associated with plaque instability, rupture, and thrombosis.Specialised pro-resolving mediators (SPMs), a class of bioactive lipid mediators derived from omega-3 fatty acids, play a critical role in orchestrating the resolution of inflammation. SPMs enhance macrophage efferocytosis, suppress pro-inflammatory signalling pathways, and promote tissue repair and vascular homeostasis. Importantly, advanced atherosclerotic plaques exhibit impaired SPM biosynthesis and an imbalance between pro-inflammatory and pro-resolving lipid mediators, contributing to persistent inflammation and defective clearance of dying cells.This chapter examines the interplay between vascular inflammation, impaired efferocytosis, and defective resolution pathways in atherosclerosis. It outlines the cellular and molecular mechanisms governing efferocytosis and SPM signalling and how these processes become disrupted during plaque progression. The chapter also reviews current therapeutic strategies aimed at restoring effective clearance and inflammation resolution, including SPM-based approaches and targeting efferocytosis pathways, and discusses emerging translational opportunities for stabilising atherosclerotic plaques and reducing cardiovascular risk.