Chemokine Signaling in Atherosclerotic Disease

Atherosclerosis arises from chronic inflammation of the arterial wall, where chemokines orchestrate the recruitment, activation and retention of immune cells. These small signalling proteins, binding to G-protein coupled receptors on leukocytes, direct monocytes, T lymphocytes and dendritic cells into developing plaques. Within these lesions, chemokine gradients promote foam-cell formation by macrophages, polarise T-cell subsets and influence the stability of the fibrous cap. Dysregulated chemokine signalling accelerates lipid accumulation, neovascularisation and extracellular matrix remodelling, heightening the risk of plaque rupture and acute cardiovascular events. Recent advances have elucidated non-canonical receptor interactions, heteromeric complexes and cross-talk with metabolic pathways, linking chemokine networks to both the initiation and progression of atherosclerotic disease. Understanding these mechanisms underpins novel therapeutic strategies, from chemokine antagonists to targeted immunomodulation, with the potential to reduce atherogenesis and improve clinical outcomes.

Research from Nature Portfolio

Recent studies have uncovered an unexpected receptor pathway in which CCL17, traditionally signalling via CCR4, engages CCR8 to induce CCL3 secretion and suppress protective regulatory T-cell functions. This non-canonical axis promotes plaque growth by limiting Treg-mediated tolerance and shaping local inflammatory milieus, while genetic disruption of CCL3 or CCR8 restores Treg numbers and retards lesion development in murine models. Another key development demonstrates that the formation of CCL5–CXCL4 heteromers intensifies leukocyte recruitment and neutrophil extracellular trap formation following ischaemic injury. A bespoke inhibitor that selectively blocks this chemokine heteromerisation attenuates inflammation, reduces infarct size and preserves cardiac function after reperfusion injury, highlighting the therapeutic promise of disrupting chemokine complexes to control vascular inflammation.

Chemokine Signaling in Atherosclerotic Disease publication trend

The graph below shows the total number of articles in chemokine signaling in atherosclerotic disease across all publications each year (not limited to Nature Index journals).

Technical terms

Chemokine: Small secreted protein that guides cell migration via receptor binding.

Chemokine receptor: Membrane G-protein coupled receptor transmitting chemokine signals.

Atherosclerotic plaque: Lipid-rich lesion in the arterial wall characterised by inflammatory infiltrates.

Regulatory T cell (Treg): Lymphocyte subset that suppresses immune activation and maintains tolerance.

Heteromerisation: Assembly of two chemokines into a functional complex with distinct activity.

Chemotaxis: Directed cell movement along a chemokine concentration gradient.

References

1. Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. Nature Cardiovascular Research (2024).
2. Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis. Scientific Reports (2018).
3. CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization. Frontiers in Immunology (2024).
4. Cytokine Profiling of Plasma and Atherosclerotic Plaques in Patients Undergoing Carotid Endarterectomy. International Journal of Molecular Sciences (2024).
5. CCL4 Inhibition in Atherosclerosis: Effects on Plaque Stability, Endothelial Cell Adhesiveness, and Macrophages Activation. International Journal of Molecular Sciences (2020).