Macrophage Autophagy in Atherosclerosis Progression

Atherosclerosis is a chronic inflammatory disorder of the arterial wall driven by lipid accumulation, immune activation and impaired cellular homeostasis. Macrophages infiltrate nascent plaques, internalise modified lipoproteins and become lipid-laden foam cells. Autophagy, the process by which cells sequester and degrade damaged organelles and protein aggregates via lysosomes, is central to macrophage lipid handling, survival and inflammatory control. In early lesions, basal autophagy facilitates cholesterol efflux and limits oxidative stress, thereby exerting an atheroprotective effect. However, during plaque progression, autophagic flux becomes compromised: lysosomal dysfunction, overwhelmed degradative capacity and dysregulated signalling pathways converge to impair autophagosome formation and clearance. This defect promotes foam cell necrosis, secondary inflammation and plaque instability. Restoration of macrophage autophagy has emerged as a promising therapeutic strategy, aiming to enhance lipid clearance, reduce pro-inflammatory cytokine release and stabilise vulnerable plaques. Recent advances have elucidated key regulators of autophagy–lysosomal biogenesis, interconnections with metabolic sensors and novel methods to stimulate macrophage degradative capacity in vivo.

Research from Nature Portfolio

Recent studies have demonstrated that amplifying the transcriptional regulator TFEB in plaque macrophages can reverse autophagy dysfunction and attenuate lesion development. Activation of TFEB restores lysosomal biogenesis, promotes the clearance of p62-rich protein aggregates and reduces macrophage apoptosis and interleukin-1β secretion. This approach leads to diminished plaque burden and enhanced stability in experimental models. In parallel, natural trehalose has been shown to induce TFEB-mediated autophagy, recapitulating the benefits of genetic TFEB overexpression and offering a practical route toward pharmacological enhancement of macrophage degradative pathways.

Macrophage Autophagy in Atherosclerosis Progression publication trend

The graph below shows the total number of articles in macrophage autophagy in atherosclerosis progression across all publications each year (not limited to Nature Index journals).

Technical terms

Autophagy: A conserved cellular process for degrading and recycling cytoplasmic components via autophagosomes and lysosomes.

Macrophage: A type of immune cell that engulfs pathogens, cellular debris and lipids within arterial plaques.

Foam cell: A lipid-engorged macrophage found in atherosclerotic plaques, formed by uptake of oxidised lipoproteins.

Transcription factor EB (TFEB): A master regulator of lysosomal biogenesis and autophagy gene networks.

Cholesterol efflux: The process by which cells export excess cholesterol, often via transporters such as ABCA1 and ABCG1.

Atherosclerotic plaque: A lesion in the arterial intima composed of lipids, immune cells, extracellular matrix and necrotic debris.

References

1. Macrophage Autophagy in Atherosclerosis. Mediators of Inflammation (2013).
2. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nature Communications (2017).
3. Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis. Journal of Nanobiotechnology (2023).
4. Vascular Electrical Stimulation with Wireless, Battery‐Free, and Fully Implantable Features Reduces Atherosclerotic Plaque Formation Through Sirt1‐Mediated Autophagy. Small (2023).
5. Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway. Cell Death & Disease (2021).