Toll-Like Receptor Signaling in Atherosclerosis

Atherosclerosis arises from chronic inflammation and lipid accumulation within arterial walls. Toll-like receptors (TLRs), a class of pattern-recognition receptors, detect both pathogen-associated molecular patterns and endogenous danger signals released from injured tissues. Engagement of TLRs on endothelial cells, monocytes/macrophages and vascular smooth muscle cells triggers intracellular cascades, principally through MyD88- and TRIF-dependent pathways, culminating in activation of NF-κB, MAPKs and production of pro-inflammatory cytokines. In early lesions, endothelial TLR activation promotes the recruitment of monocytes and upregulation of adhesion molecules. Within plaques, TLR-driven signals alter macrophage cholesterol handling, favour foam cell formation and amplify inflammasome assembly. In smooth muscle cells, TLR engagement induces cytokine release and migration into the intima. Collectively, these responses accelerate plaque growth, destabilisation and the risk of thrombotic events. Therapeutic modulation of TLR signalling holds promise for attenuating vascular inflammation and stabilising plaques, with strategies ranging from selective receptor antagonists to modulation of downstream adaptors and transcription factors.

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Toll-Like Receptor Signaling in Atherosclerosis publication trend

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Technical terms

Toll-like receptor (TLR): Pattern-recognition receptor that senses microbial molecules or host-derived danger signals and initiates innate immune responses.

Atherosclerosis: Chronic disease characterised by lipid and immune cell accumulation within arterial walls, leading to plaque formation and vascular occlusion.

Foam cell: Lipid-laden macrophage within atherosclerotic lesions derived from uptake of modified low-density lipoproteins.

Cholesterol efflux: Cellular process exporting excess cholesterol via transporters (e.g., ABCA1, ABCG1) to extracellular acceptors, preventing foam cell formation.

MyD88-dependent pathway: Signalling cascade used by most TLRs involving the adaptor MyD88, leading to NF-κB activation and pro-inflammatory cytokine production.

References

1. Toll-Like Receptors in Atherosclerosis. International Journal of Molecular Sciences (2013).
2. Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation. International Journal of Molecular Sciences (2024).
3. Unveiling the therapeutic potential of miR‐146a: Targeting innate inflammation in atherosclerosis. Journal of Cellular and Molecular Medicine (2024).
4. Infection and atherosclerosis: TLR-dependent pathways. Cellular and Molecular Life Sciences (2020).