Correction: involvement of TNF-α converting enzyme in the development of psoriasis-like lesions in a mouse model.

[This corrects the article DOI: 10.1371/journal.pone.0112408.]

Involvement of TNF-α Converting Enzyme in the Development of Psoriasis-Like Lesions in a Mouse Model

<div><p>TNF-α plays a crucial role in psoriasis; therefore, TNF inhibition has become a gold standard for the treatment of psoriasis. TNF-α is processed from a membrane-bound form by TNF-α converting enzyme (TACE) to soluble form, which exerts a number of biological activities. EGF receptor (EGFR) ligands, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and transforming growth factor (TGF)-α are also TACE substrates and are psoriasis-associated growth factors. Vascular endothelial growth factor (VEGF), one of the downstream molecules of EGFR and TNF signaling, plays a key role in angiogenesis for developing psoriasis. In the present study, to assess the possible role of TACE in the pathogenesis of psoriasis, we investigated the involvement of TACE in TPA-induced psoriasis-like lesions in K5.Stat3C mice, which represent a mouse model of psoriasis. In this mouse model, TNF-α, amphiregulin, HB-EGF and TGF-α were significantly up-regulated in the skin lesions, similar to human psoriasis. Treatment of K5.Stat3C mice with TNF-α or EGFR inhibitors attenuated the skin lesions, suggesting the roles of TACE substrates in psoriasis. Furthermore, the skin lesions of K5.Stat3C mice showed down-regulation of tissue inhibitor of metalloproteinase-3, an endogenous inhibitor of TACE, and an increase in soluble TNF-α. A TACE inhibitor abrogated EGFR ligand-dependent keratinocyte proliferation and VEGF production in vitro, suggesting that TACE was involved in both epidermal hyperplasia and angiogenesis during psoriasis development. These results strongly suggest that TACE contributes to the development of psoriatic lesions through releasing two kinds of psoriasis mediators, TNF-α and EGFR ligands. Therefore, TACE could be a potential therapeutic target for the treatment of psoriasis.</p></div

Expression of TACE and TNF-α in the development of psoriasis-like skin lesions in K5.Stat3C mice.

<p>(A–C), Representative histology and immunohistochemistry of human skins (A), ear skins in K5.Stat3C mice (B), and wild-type mice (C). non-pso, non-psoriasis control; TPA, TPA-treated ear skins sampled at day 3; Hematoxylin and eosin staining (H&E, top panels), Immunohistochemical staining for TACE (middle panels) and TNF-α (bottom panels). Arrow, intraepidermal pustule of neutrophils. Bars = 100 µm (human), 50 µm (mouse). (D–F), epidermal thickness (D), TNF-α mRNA expression (E) and TNF-α protein levels (F) in the TPA-treated ear skins of K5.Stat3C mice (black bars) and wild-type mice (white bars). Data represent means ± SD of 3 to 8 mice. *<i>p</i><0.05, **<i>p</i><0.01, versus K5.Stat3C mice at day 0, ^†<i>p</i><0.05, ^††<i>p</i><0.01, versus wild-type mice at day 0, by Dunnett’s test.</p

Down-regulation of TIMP-3, an endogenous TACE inhibitor, and TACE enzymatic activity in the development of psoriasis-like skin lesions.

<p>(A), Gene expression of TIMP-3 in the TPA-treated ear skins of K5.Stat3C mice (black bars) and wild-type mice (white bars). Data represent means ± SD of 3 to 8 mice. **<i>p</i><0.01, versus K5.Stat3C mice at day 0, ^††<i>p</i><0.01, versus wild-type mice at day 0, by Dunnett’s test. (B), Western blot analysis of TIMP-3 in ear skins of K5.Stat3C mice collected before TPA application (0) or 6 h (0.25) after TPA application. (C), Western blot analysis of soluble TNF-α (sTNF-α), which is around 17 kDa of molecular size, in the lysates from ear skins of K5.Stat3C mice compared with wild-type mice. The ear skins were collected before TPA application (0) or at 6 h (0.25) and 1 day (1) after TPA application. C, Control of soluble TNF-α. (D), Enzymatic activity of TACE in ear skins of K5.Stat3C mice versus wild-type mice; untreated control (white bars) and TPA-treated at 6h of the second TPA application (black bars). Enzymatic activity in skins was indicated as ratio to that in untreated wild-type skins. Data represent means ± SD of 4 to 5 mice, **<i>p</i><0.01; n.s., not significant by Tukey-Kramer’s test.</p

Involvement of TNF-α in the development of psoriasis-like skin lesions in K5.Stat3C mice.

<p>(A), Ear thickness (Δmm) ± SD following topical TPA in mice treated with control IgG (n = 6, squares) and etanercept (n = 6, triangles). *<i>p</i><0.05, **<i>p</i><0.01, versus control IgG, by Student’s <i>t</i>-test. (B), Representative histology of ear skins from K5.Stat3C mice treated with control IgG (top) and etanercept (bottom). H&E staining. Bar = 100 µm. (C–E), Inhibitory effect of etanercept (Etn) on TPA-induced epidermal hyperplasia (C), gene expression of IL-17A (D), and IL-12/23p40 (E) in ear skins. Data represent means ± SD of 3 to 6 mice. *<i>p</i><0.05, **<i>p</i><0.01, versus control IgG, by Student’s <i>t</i>-test.</p