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

Abstract

Background-Interferon (IFN)-␣ is a pluripotent inflammatory cytokine typically induced by viral infections. In rupture-prone atherosclerotic plaques, plasmacytoid dendritic cells produce IFN-␣. In the present study we explored the contribution of IFN-␣ to inflammation and tissue injury in the plaque microenvironment.

Endothelial cell-derived microparticles induce plasmacytoid dendritic cell maturation: potential implications in inflammatory diseases

“…Such IFN-α secretion is notably found in systemic lupus erythematosus, 42,43 psoriasis 23,32 and in atherosclerotic plaques. 27,28 In our study, EMP did not cause PDC to secrete IFN-α. A first hypothesis to explain this is that PDC activation by EMP may be insufficient to induce IFN-α secretion.…”

“…3,8,[14][15][16][17][18][19][20][21][23][24][25][26][27][28] We, therefore, hypothesized that EMP could trigger PDC maturation and that such an interaction could contribute to the above mentioned inflammatory disorders. Here, we demonstrate that EMP can indeed induce PDC maturation, as shown by co-stimulatory molecule upregulation, inflammatory cytokine secretion, and by allogeneic naive CD4 + T-cell proliferation.…”

“…The PDC:EMP ratio used here (1:10) corresponds to 5000 EMP/µL, an EMP concentration found in vivo in pathological situations. 35,36 Infiltration of mature PDC in injured tissues (such as in atherosclerotic plaques, [26][27][28] in the skin in psoriasis 23,32 or systemic lupus erythematosus) 24,25 has been observed in several chronic inflammatory diseases. Increased expression of the chemokine receptor CCR7 40 -as observed here -has also been reported in trapped dendritic cells found in atherosclerotic plaques.…”

“…[23][24][25] In addition, PDC have been found in the atherosclerotic plaques. [26][27][28] However, a growing body of data shows that PDC can also be involved in tolerance induction. [29][30][31] On the other hand in vitro activation of immature human PDC with ligands for Toll-like receptor (TLR) 7 or TLR9 (e.g., R848 or type A CpG motifs, respectively) leads to proinflammatory cytokine production and to increased co-stimulatory molecule expression, subsequently inducing naive T-cell activation.…”

Role Of Toll Like Receptors In Various Diseases

“…78 Aterosklerotik plakta bulunan dendritik hücrelerden TLR 4 aktivasyonu sonucu salınan IFN-alfa, TNF-alfa, IL-12 ve MMP-9 gibi mediatörler, plağın rüptüre olmasında, dolayısıyla akut myokardial enfarktüsün gelişmesinde önemli rol oynar. 79 Trombositlerin üzerinde bulunan TLR 2 ve 4'lerin sentetik ligandlarla uyarılması sonucu trombosit adhezyonu ve agregasyonundaki artışın, tromboz gelişimine katkısı olduğunu gösterilmiştir. 80,81 Ayrıca kardiomyositlerde TLR 2, 4 ve 5 aktivasyonuyla oluşan sinyalizasyonun myokardın kontraktilitesini azalttığı ve kalp yetmezliğinde etkili olduğu gösterilmiştir.…”