Dendritic Cell Modulation in Atherosclerosis Pathogenesis

Atherosclerosis is a chronic inflammatory disorder of the arterial wall, driven by lipid retention, endothelial dysfunction and immune cell infiltration. Dendritic cells (DCs) occupy a pivotal role in bridging innate sensing of modified lipids and necrotic debris with adaptive T-cell responses. Distinct DC subsets within plaques—such as CD11b+ myeloid DCs and plasmacytoid DCs—can either promote pro-inflammatory T helper 1 and Th17 responses or foster regulatory tolerance through induction of Treg expansion. Local microenvironmental cues, including oxidised low-density lipoprotein and disturbed shear stress, shape DC maturation, cytokine secretion and migratory behaviour. Intracellular pathways, notably autophagy, further govern DC antigen-processing capabilities and determine their capacity to modulate plaque stability. Enzymes that remodel the extracellular matrix may augment DC recruitment and activation, perpetuating vascular inflammation. Therapeutic targeting of DC differentiation, antigen-presentation mechanisms and intracellular signalling holds promise for rebalancing immune responses, slowing plaque progression and reducing cardiovascular events.

Research from Nature Portfolio

A key investigation employing Batf3-deficient chimeric mice revealed that loss of CD8α+ DCs sharply impairs cross-presentation to CD8+ T cells without altering lesion development or plaque stability. Despite markedly reduced cross-priming capacity, atherosclerotic burden, necrotic core formation and collagen content remained unchanged, indicating that cross-presentation by this specialised DC subset is not essential for plaque initiation or progression. These findings challenge the presumed centrality of CD8α+ DC-mediated cytotoxic T-cell activation in destabilising advanced lesions and suggest that other antigen-presentation pathways or DC subsets may underlie immunopathogenesis in atherosclerosis.

Research from all publishers

In a 2024 study using a heparanase-deficient ApoE-knockout model, absence of this extracellular matrix-degrading enzyme led to diminished recruitment of DCs to the aortic wall and a marked reduction in early lesion size and necrotic core formation. Reduced aortic levels of vascular cell adhesion molecule-1 and circulating chemokines were accompanied by lowered DC counts, highlighting a link between matrix remodelling, DC trafficking and plaque initiation.

A comprehensive 2024 review of immune cell heterogeneity in atherosclerotic plaques emphasised the emerging role of DCs in orchestrating immune cell cross-talk. High-dimensional profiling has uncovered multiple DC phenotypes within human and murine plaques, each characterised by unique patterns of cytokine secretion and T-cell priming. This work has underscored the necessity of resolving DC subset dynamics to identify precise immunomodulatory targets.

An earlier investigation demonstrated that disruption of autophagy in CD11b+ DCs promotes a tolerogenic phenotype, enhances regulatory T-cell expansion and limits atherogenesis in LDL receptor–deficient mice. Autophagy-deficient DCs exhibited increased transforming growth factor-β signalling and diminished Th1 responses, resulting in attenuated plaque development and preserved vascular homeostasis.

Dendritic Cell Modulation in Atherosclerosis Pathogenesis publication trend

The graph below shows the total number of articles in dendritic cell modulation in atherosclerosis pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Dendritic cell (DC): A professional antigen-presenting leukocyte that links innate detection of danger signals to adaptive T-cell activation within vascular tissues.

Cross-presentation: A process whereby DCs present extracellular antigens via MHC class I molecules to prime CD8+ T-cell responses.

Autophagy: An intracellular degradation pathway that recycles cellular components, modulating antigen processing and cytokine production in immune cells.

Atherosclerotic plaque: A focal lesion in the arterial intima composed of lipid-laden foam cells, immune infiltrates, extracellular matrix and a necrotic core.

Regulatory T cell (Treg): A subset of CD4+ T lymphocytes that suppresses immune activation and contributes to resolution of vascular inflammation.

References

1. Immunological perspectives on atherosclerotic plaque formation and progression. Frontiers in Immunology (2024).
2. Heparanase promotes the onset and progression of atherosclerosis in apolipoprotein E gene knockout mice. Atherosclerosis (2024).
3. Impaired Autophagy in CD11b+ Dendritic Cells Expands CD4+ Regulatory T Cells and Limits Atherosclerosis in Mice. Circulation Research (2019).
4. Ablation of CD8α+ dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice. Scientific Reports (2015).