IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis.
Keratinocytes play a key role in innate immune responses of the skin to bacterial and viral pathogens. Viral double-stranded RNA and its synthetic analogue polyriboinosinic-polyribocytidylic acid (poly-IC) are recognized via multiple pathways involving the receptors Toll-like receptor 3 (TLR3), protein kinase R (PKR), and the recently described cytosolic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We show that preincubation of human keratinocytes with IFN-alpha enhances the proinflammatory responses to poly-IC. Kinetic studies suggest that this is mediated via upregulation of the receptors TLR3, PKR, RIG-I, and MDA5. Interestingly, expression of RIG-I, MDA5, and PKR was significantly increased in lesional skin from patients with psoriasis, a chronic inflammatory skin disease that is characterized by high IFN-alpha levels. These results suggest that psoriatic keratinocytes show increased sensitivity to viral RNA intermediates, thereby leading to excessive proinflammatory responses and maintenance of the inflammatory skin phenotype. Here, we provide early evidence that point toward a role for the recently described cytosolic innate RNA receptors in non-viral chronic inflammatory diseases.
Prens
Errol P
EP
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. e.prens@erasmusmc.nl
Kant
Marius
M
van Dijk
Grietje
G
van der Wel
Leontine I
LI
Mourits
Sabine
S
van der Fits
Leslie
L
D003600:Cytosol / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000494:pharmacology; D012367:RNA, Viral / Q000276:immunology* / Q000494:pharmacology; D011971:Receptors, Immunologic; D011991:Receptors, Virus / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D016898:Interferon-alpha; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D019892:eIF-2 Kinase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C