Background/Purpose: Psoriasis is a T-cell-mediated immunological skin disease with a complex pathogenesis where both genetic and environmental factors are involved. Interferon regulatory factor (IRF)-2 is one of the potential susceptibility genes for psoriasis. IRFs are a family of transcription factors that regulate expression of pro- and anti-inflammatory genes. IRF-2 protein binds the same regulatory sequence as IRF-1, which suppresses transcription of interferon-inducible genes. Topical application of imiquimod, a TLR7/8 ligand, induces psoriasis-like inflamed skin lesions via the IL-17/23 axis. We hypothesized that combination of IRF2 gene status and environmental stimulus (imiquimod) would cause severer skin lesions, serving as a good model of human psoriasis.

Methods: IRF-2^+/- and wild-type (WT) mice received a daily topical dose of 62.5 mg imiquimod cream (5%) on a shaved back and ears for 6 consecutive days. Erythema, scaling, and skin thickness were independently scored every day. Total RNA was isolated from skin specimens on day 2 and 5 and reverse-transcribed into cDNA. Macrophage were harvested from peritoneal cavity of naive IRF-2^+/- and WT mice and stimulated with 1 or 5 μg/ml of imiquimod for 6 or 24 hours in vitro. Total RNA was isolated and reverse-transcribed into cDNA. Messenger RNA expression of different cytokines was analyzed using a real-time PCR quantification method.

Results: Imiquimod-induced skin inflammation assessed by erythema, scaling, and skin thickness was severer in IRF-2^+/- mice than WT mice. In inflamed skin, mRNA expression of TNF-α, IL-12/23p40, IL-23p19, and inducible nitric oxide synthase (iNOS) was increased on day 2, and that of TNF-α, IL-12p35, IL-17A, and iNOS was increased on day 5 in IRF-2^+/- mice compared to WT mice. In peritoneal macrophage of IRF-2^+/- and WT mice stimulated with imiquimod, mRNA levels of TNF-α, IL-12/23p40, IL-23p19, IL-12p35, IL-36α, and IL-36γ were significantly elevated compared to non-stimulated macrophages. Interestingly, macrophages harvested from IRF-2^+/- mice expressed higher levels of TNF-α, IL-12/23p40, IL-23p19 compared to those from WT mice 24 hours after stimulation, while they expressed similar levels of IL-12p35, IL-36α, and IL-36γ. Moreover, elevated mRNA expression of iNOS was observed only in stimulated macrophages derived from IRF-2^+/- mice.

Conclusion: These results suggest that IRF-2 haploinsufficiency and a TLR7/8 stimulator regulate cytokine expression in a different manner, developing Th17-associated skin inflammation, which may serve as a good model of human psoriasis.

---

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-regulatory-factor-2-haploinsufficiency-deteriorates-imiquimod-induced-psoriasis-like-skin-inflammation/