Synergistic proinflammatory effects of the antiviral cytokine interferon-alpha and Toll-like receptor 4 ligands in the 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.


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.
Niessner
Alexander
A
Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Shin
Min Sun
MS
Pryshchep
Olga
O
Goronzy
Jörg J
JJ
Chaikof
Elliot L
EL
Weyand
Cornelia M
CM
D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology*; D008024:Ligands; D008297:Male; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D000998:Antiviral Agents; D018836:Inflammation Mediators; D016898:Interferon-alpha; D008024:Ligands; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4