IRF-2 haploinsufficiency causes enhanced imiquimod-induced psoriasis-like skin inflammation

• Published in: Journal of dermatological science 2018-04, Vol.90 (1), p.35-45
• Main Authors: Kawaguchi, Makiko, Oka, Tomonori, Sugaya, Makoto, Suga, Hiraku, Kimura, Takayuki, Morimura, Sohshi, Fujita, Hideki, Sato, Shinichi
• Format: Article
• Language: English
• Subjects: Aminoquinolines - immunology; Aminoquinolines - pharmacology; Animals; Disease Models, Animal; Haploinsufficiency; Humans; Imiquimod; Interferon Regulatory Factor-2 - genetics; Interferon Regulatory Factor-2 - metabolism; Interferon-alpha - genetics; Interferon-alpha - metabolism; IRF-2; Keratinocytes - metabolism; Macrophages - drug effects; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic - genetics; Nitric Oxide Synthase Type II - metabolism; Psoriasis; Psoriasis - genetics; Psoriasis - immunology; Psoriasis - pathology; RNA, Messenger - metabolism; Severity of Illness Index; Skin - blood supply; Skin - cytology; Skin - pathology
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2017.12.014

•IRF-2 haploinsufficiency exacerbates IMQ-induced psoriasis-like dermatitis in mice.•IMQ treatment induces enhanced cytokine expression by macrophages from IRF-2+/− mice.•Enhanced angiogenesis and iNOS expression are observed in IMQ-treated IRF-2+/− mice. IFN regulatory factor (IRF)-2 is one of the potential susceptibility genes for psoriasis, but how this gene influences psoriasis pathogenesis is unclear. Topical application of imiquimod (IMQ), a TLR7 ligand, induces psoriasis-like skin lesions in mice. The aim of this study was to investigate whether IRF-2 gene status would influence severity of skin disease in IMQ-treated mice. Imiquimod-induced psoriasis-like skin inflammation was assessed by clinical findings, histology, and cytokine expression. The effects of imiquimod or IFN on peritoneal macrophages were analyzed in vitro. IMQ-induced skin inflammation assessed by clinical findings and histology was more severe in IRF-2+/− mice than in wild-type mice. In inflamed skin, mRNA expression levels of tumor necrosis factor (TNF)-α, IL-12/23p40, IL-17A, and IL-22 were significantly elevated in IRF-2+/− mice compared to wild-type mice. Stimulation of peritoneal macrophages by IMQ significantly increased mRNA levels of TNF-α, IL-12/23p40, IL-23p19, IL-12p35, and IL-36. Interestingly, macrophages from IRF-2+/− mice expressed higher levels of TNF-α, IL-12/23p40, and IL-36 compared to those from wild-type mice 24 h after stimulation, while they expressed similar levels of IL-12p35 and IL-23p19. Moreover, elevated mRNA expression of inducible nitric oxide synthase was observed only in IMQ-stimulated macrophages derived from IRF-2+/− mice, which correlated with angiogenesis in IMQ-treated ears of IRF-2+/− mice. These results suggest that IRF-2 haploinsufficiency creates heightened biologic responses to IFN-α that phenotypically lead to enhanced angiogenesis and psoriasis-like inflammation within skin.