Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice.
Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.
Inflammation Research Center, VIB, 9052 Ghent, Belgium; and Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Lynda
L
Grine
Inflammation Research Center, VIB, 9052 Ghent, Belgium; and Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Lien
L
Dejager
Inflammation Research Center, VIB, 9052 Ghent, Belgium; and Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium Roosmarijn.Vandenbroucke@irc.VIB-UGent.be Claude.Libert@irc.VIB-UGent.be.
Claude
C
Libert
Inflammation Research Center, VIB, 9052 Ghent, Belgium; and Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium Roosmarijn.Vandenbroucke@irc.VIB-UGent.be Claude.Libert@irc.VIB-UGent.be.
Roosmarijn E
http://orcid.org/0000-0002-8327-620X
RE
Vandenbroucke
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D040501:Calgranulin A / Q000378:metabolism; D000068800:Etanercept; D000077271:Imiquimod; D007074:Immunoglobulin G / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D000069285:Infliximab; D007370:Interferon Type I / Q000096:biosynthesis / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000634:Aminoquinolines; D000911:Antibodies, Monoclonal; D040501:Calgranulin A; C508032:Ifnar1 protein, mouse; D007074:Immunoglobulin G; D007370:Interferon Type I; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C086145:S100a8 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D000069285:Infliximab; D000068800:Etanercept; D000077271:Imiquimod