Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

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Abstract
Background— Interferon (IFN)-α is a pluripotent inflammatory cytokine typically induced by viral infections. In rupture-prone atherosclerotic plaques, plasmacytoid dendritic cells produce IFN-α. In the present study we explored the contribution of IFN-α to inflammation and tissue injury in the plaque microenvironment. Methods and Results— In 53% of carotid plaques (n=30), CD123 + plasmacytoid dendritic cells clustered together with CD11c + myeloid dendritic cells, a distinct dendritic cell subset specialized in sensing danger signals from bacteria and tissue breakdown. Tissue concentrations of IFN-α and tumor necrosis factor (TNF)-α transcripts were tightly correlated ( r =0.76, P P P P P Conclusions— In the atherosclerotic plaque, IFN-α functions as an inflammatory amplifier. It sensitizes antigen-presenting cells toward pathogen-derived TLR4 ligands by upregulating TLR4 expression and intensifies TNF-α, interleukin-12, and matrix metalloproteinase-9 production, all implicated in plaque destabilization. Thus, IFN-α–inducing pathogens, even when colonizing distant tissue sites, threaten the stability of inflamed atherosclerotic plaque.

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