Synergistic proinflammatory effects of the antiviral cytokine interferon-α and toll-like receptor 4 ligands in the atherosclerotic plaque

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<0.001), suggesting a regulatory role of IFN-α in TNF-α production. Plaque tissue stimulation with CpG ODN, a Toll-like receptor (TLR) 9 ligand, increased IFN-α production (57.8±23.7 versus 25.9±8.6 pg/mL; P<0.001), whereas the TLR4 ligand lipopolysaccharide induced TNF-α secretion (225.1±3.0 versus 0.7±0.2 pg/mL; P<0.001). Treating plaque tissue with IFN-α markedly enhanced lipopolysaccharide-triggered TNF-α secretion (559.0±25.9 versus 225.1±3.0 pg/mL; P<0.001). IFN-α pretreatment also amplified the effects of lipopolysaccharide on interleukin-12, interleukin-23, and matrix metalloproteinase-9, suggesting that the antiviral cytokine sensitized myeloid dendritic cells and macrophages toward TLR4 ligands. Mechanistic studies demonstrated that IFN-α modulated the myeloid dendritic cell response pattern by upregulating TLR4 expression (P<0.001) involving both the STAT (signal transducer and activator of transcription) and the PI(3)K pathway. 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.