BACKGROUND: Interferon (IFN)-alpha is a pluripotent inflammatory cytokine typically induced by viral infections. In rupture-prone atherosclerotic plaques, plasmacytoid dendritic cells produce IFN-alpha. In the present study we explored the contribution of IFN-alpha 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-alpha and tumor necrosis factor (TNF)-alpha transcripts were tightly correlated (r=0.76, P<0.001), suggesting a regulatory role of IFN-alpha in TNF-alpha production. Plaque tissue stimulation with CpG ODN, a Toll-like receptor (TLR) 9 ligand, increased IFN-alpha production (57.8+/-23.7 versus 25.9+/-8.6 pg/mL; P<0.001), whereas the TLR4 ligand lipopolysaccharide induced TNF-alpha secretion (225.1+/-3.0 versus 0.7+/-0.2 pg/mL; P<0.001). Treating plaque tissue with IFN-alpha markedly enhanced lipopolysaccharide-triggered TNF-alpha secretion (559.0+/-25.9 versus 225.1+/-3.0 pg/mL; P<0.001). IFN-alpha 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-alpha 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-alpha functions as an inflammatory amplifier. It sensitizes antigen-presenting cells toward pathogen-derived TLR4 ligands by upregulating TLR4 expression and intensifies TNF-alpha, interleukin-12, and matrix metalloproteinase-9 production, all implicated in plaque destabilization. Thus, IFN-alpha-inducing pathogens, even when colonizing distant tissue sites, threaten the stability of inflamed atherosclerotic plaque.
BACKGROUND:Interferon (IFN)-alpha is a pluripotent inflammatory cytokine typically induced by viral infections. In rupture-prone atherosclerotic plaques, plasmacytoid dendritic cells produce IFN-alpha. In the present study we explored the contribution of IFN-alpha 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-alpha and tumor necrosis factor (TNF)-alpha transcripts were tightly correlated (r=0.76, P<0.001), suggesting a regulatory role of IFN-alpha in TNF-alpha production. Plaque tissue stimulation with CpG ODN, a Toll-like receptor (TLR) 9 ligand, increased IFN-alpha production (57.8+/-23.7 versus 25.9+/-8.6 pg/mL; P<0.001), whereas the TLR4 ligand lipopolysaccharide induced TNF-alpha secretion (225.1+/-3.0 versus 0.7+/-0.2 pg/mL; P<0.001). Treating plaque tissue with IFN-alpha markedly enhanced lipopolysaccharide-triggered TNF-alpha secretion (559.0+/-25.9 versus 225.1+/-3.0 pg/mL; P<0.001). IFN-alpha 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-alpha 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-alpha functions as an inflammatory amplifier. It sensitizes antigen-presenting cells toward pathogen-derived TLR4 ligands by upregulating TLR4 expression and intensifies TNF-alpha, interleukin-12, and matrix metalloproteinase-9 production, all implicated in plaque destabilization. Thus, IFN-alpha-inducing pathogens, even when colonizing distant tissue sites, threaten the stability of inflamed atherosclerotic plaque.
Authors: Christian Erbel; Mohammadreza Akhavanpoor; Deniz Okuyucu; Susanne Wangler; Alex Dietz; Li Zhao; Konstantinos Stellos; Kristina M Little; Felix Lasitschka; Andreas Doesch; Maani Hakimi; Thomas J Dengler; Thomas Giese; Erwin Blessing; Hugo A Katus; Christian A Gleissner Journal: J Immunol Date: 2014-09-26 Impact factor: 5.422
Authors: Mark W Majesky; Xiu Rong Dong; Virginia Hoglund; William M Mahoney; Guenter Daum Journal: Arterioscler Thromb Vasc Biol Date: 2011-07 Impact factor: 8.311
Authors: C A Wijbrandts; S I van Leuven; H D Boom; D M Gerlag; E G S Stroes; J J P Kastelein; P P Tak Journal: Ann Rheum Dis Date: 2008-08-22 Impact factor: 19.103