Anti-Atherogenic Mechanisms and Therapies

Abstract

Purpose of review: This review examines anti-atherogenic mechanisms and the crucial role of efferocytosis in promoting inflammation resolution, with a focus on innovative, resolution-based therapeutic strategies that aim to restore vascular homeostasis and mitigate atherosclerosis progression.

Recent findings: Atherosclerosis, a chronic inflammatory condition, is exacerbated by impaired efferocytosis, which contributes to plaque instability and the expansion of the necrotic core. Advanced molecular and cellular profiling has revealed diverse macrophage populations and their metabolic adaptations during efferocytosis, which drive the production of resolving mediators essential for tissue repair. Dysregulated signaling and metabolic pathways disrupt the efficient clearance of apoptotic cells, exacerbating inflammation. Molecular regulators, such as microRNAs, further impact efferocytosis, governing cardiovascular outcomes. Resolution-based therapies, including specialized pro-resolving mediators, peptides, and metabolites, enhance the successive clearance of apoptotic cells while maintaining host immune function, offering advantages over traditional immunosuppressive approaches. Additionally, vaccines targeting disease-specific antigens show promise in eliciting protective immune responses that can help ameliorate atherosclerosis. Efferocytosis is a key regulator of inflammation resolution in atherosclerosis, linking macrophage metabolism to plaque stability. Its disruption drives disease progression, but emerging therapies targeting resolution pathways, metabolic reprogramming, and immune modulation hold the potential for effective interventions. Advances in profiling technologies and targeted delivery systems will address translational challenges, paving the way for precision medicine in treating atherosclerotic cardiovascular disease.

Keywords: Atherosclerosis; Efferocytosis; Efferotabolism; Inflammation resolution; Macrophage metabolism; Pro-resolving mediators.

Fig. 1

Immune regulation of efferocytosis in stable and unstable atherosclerotic plaques. In stable plaques, effective efferocytosis by pro-resolving macrophages preserves plaque integrity. This process is supported by regulatory T cells, protective natural IgM antibodies, and macrophage subsets expressing apoptotic cell (AC) receptors. ACs are recognized directly via phosphatidylserine-binding receptors such as TIMs and Stabilins, or indirectly via bridging molecules (e.g., MFG-E8, GAS6, Protein S) that link phosphatidylserine or calreticulin to MerTK, integrins (αvβ3/αvβ5), and LRP1. In contrast, unstable plaques in advanced disease are characterized by a shift toward pro-inflammatory immune responses, including Th1 and Th17 cells, IgG-switched antibodies, and macrophages that generate reactive oxygen species. These inflammatory cues impair the clearance of dead cells through multiple mechanisms: proteolytic cleavage of MerTK and LRP1 by ADAMs and MMPs; downregulation of bridging molecules such as GAS6 and MFG-E8; and increased expression of “don’t-eat-me” signals such as CD47, which inhibit phagocytic uptake via SIRPα signaling. Impaired clearance promotes post-apoptotic necrosis, expansion of the necrotic core, and thinning of the fibrous cap, thereby driving plaque instability