Dendritic cells in atherosclerosis: integrating ontogeny, functional states, spatial organization, and therapeutic implications

Abstract

Atherosclerosis arises from the interaction between lipid accumulation and sustained innate and adaptive immune activation, and residual cardiovascular risk despite intensive lipid-lowering therapy underscores the need to clarify vascular inflammatory mechanisms. Dendritic cells (DCs) link antigen sensing and presentation to T-cell regulation, but their roles in atherosclerosis remain incompletely resolved. This review synthesizes evidence on conventional type 1 and type 2 DCs, plasmacytoid DCs, and monocyte-derived DC-like cells using a lineage–state–location–validation framework that asks which cells are present, which functional programs they exhibit, where they are located, and what evidence supports the proposed function. Current evidence indicates that lineage defines functional potential but does not determine pathological activity; lipid loading, oxidative and metabolic stress, extracellular nucleic acids, cytokines, anatomical compartment, and disease stage can shift DCs toward inflammatory, regulatory, or dysfunctional states. Single-cell and spatial profiling have improved resolution of plaque-associated myeloid populations, but rare human DCs, overlap with macrophages and monocytes, cross-sectional sampling, and the inability of expression or proximity to establish causality remain important limitations. Therapeutic strategies should be distinguished as direct or DC-enriched delivery, state- or pathway-directed modulation, and indirect effects on DC function. Current interventions remain preclinical and generally lack sufficient cellular or state selectivity. Future work should prioritize reproducible human DC-state identification, lineage-resolved spatial and functional validation, established-disease models, and biomarkers of pathway activity and target engagement. No specific human DC state is yet clinically actionable.