Atherosclerotic Inflammation and Immune Mechanisms

Atherosclerosis is a chronic, immune‐mediated inflammatory condition of the arterial wall that underlies the majority of cardiovascular events worldwide. It is initiated by endothelial dysfunction, which promotes retention and oxidation of lipoproteins in the subendothelial space. Circulating monocytes adhere to activated endothelium and differentiate into macrophages that engulf lipids to form foam cells, giving rise to fatty streaks. As lesions progress, both innate immune cells—macrophages, neutrophils and dendritic cells—and adaptive immune cells—T helper subsets, cytotoxic T cells and B cells—interact through costimulatory and coinhibitory signals to shape plaque composition. Key molecular pathways, including the CD40–CD40L axis and downstream TRAF–NF-κB signalling, drive production of proinflammatory cytokines such as interleukin-1β and tumour necrosis factor-α. Expansion of the necrotic core and thinning of the fibrous cap heighten risk of plaque rupture and thrombosis. Counter‐regulatory mechanisms, including regulatory T cells and specialised pro‐resolving mediators, seek to limit inflammation, but an imbalance underpins progressive lesion growth. Insights into microRNA regulators, endothelial activation and immune checkpoint pathways have revealed novel targets for immunomodulatory therapies aimed at stabilising plaques, reducing clinical events and addressing residual inflammatory risk beyond lipid‐lowering strategies.

Research from Nature Portfolio

Recent studies have dissected cell‐specific roles of the CD40–CD40L pathway. Deletion of CD40L in CD4+ T cells or CD40 in dendritic cells markedly reduces Th1‐driven interferon-γ production, leading to smaller, more stable plaques with thicker fibrous caps and fewer necrotic cores. In contrast, platelet‐restricted CD40L deficiency selectively attenuates thrombotic complications without altering plaque size, highlighting divergent functions that inform precision targeting of the CD40–CD40L dyad. Complementing these findings, a novel PPARγ-dependent microRNA circuit—miR-424/503—was shown to suppress endothelial CD40 expression and downstream inflammatory angiogenesis. Loss of this axis enhances endothelial sprouting and leukocyte recruitment, whereas PPARγ activation restores miR-424/503 levels to temper vascular inflammation and neovascular responses in experimental models.

Atherosclerotic Inflammation and Immune Mechanisms publication trend

The graph below shows the total number of articles in atherosclerotic inflammation and immune mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Endothelial dysfunction: Impaired barrier and vasoregulatory functions of the vessel lining that initiate atherosclerosis.

Macrophage: Innate immune cell that ingests lipids and debris, driving foam‐cell formation.

Foam cell: Lipid‐laden macrophage within the arterial intima and hallmark of early plaque.

CD40–CD40L axis: Costimulatory signalling pathway between immune and vascular cells promoting inflammation.

Regulatory T cell: Adaptive immune cell subset that suppresses excessive inflammation and maintains tolerance.

Cytokine: Soluble protein mediator that orchestrates immune cell recruitment and activation.

Necrotic core: Central region of advanced plaques composed of dead cells and extracellular lipids that increases vulnerability.

References

1. Role of inflammatory signaling pathways involving the CD40–CD40L–TRAF cascade in diabetes and hypertension—insights from animal and human studies. Basic Research in Cardiology (2024).
2. Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease. Nature Communications (2021).
3. A PPARγ-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis. Scientific Reports (2017).
4. Advances in immunotherapy modalities for atherosclerosis. Frontiers in Pharmacology (2023).
5. Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall. International Journal of Molecular Sciences (2024).