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  • Title: IRF-2 haploinsufficiency causes enhanced imiquimod-induced psoriasis-like skin inflammation.
    Author: Kawaguchi M, Oka T, Sugaya M, Suga H, Kimura T, Morimura S, Fujita H, Sato S.
    Journal: J Dermatol Sci; 2018 Apr; 90(1):35-45. PubMed ID: 29305258.
    Abstract:
    BACKGROUNDS: 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. OBJECTIVE: The aim of this study was to investigate whether IRF-2 gene status would influence severity of skin disease in IMQ-treated mice. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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