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. 2017 Jun 28;12(6):e0180481.
doi: 10.1371/journal.pone.0180481. eCollection 2017.

Hypomorphic A20 expression confers susceptibility to psoriasis

Anri Aki  1 , Miyuki Nagasaki  1 , Barbara Ann Malynn  2 , Averil Ma  2 , Takashi Kagari  1
Affiliations

Hypomorphic A20 expression confers susceptibility to psoriasis

Anri Aki et al. PLoS One. .

Abstract

Psoriasis is a common inflammatory skin disease that affects approximately 1% of the population worldwide. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene polymorphisms have been strongly associated with psoriasis susceptibility. In this study, we investigate how TNFAIP3, also known as A20, may regulate psoriasis susceptibility. We found that haplo-insufficient A20+/- mice develop severe toll-like receptor (TLR)-induced skin inflammation compared to wild type mice owing to amplified production of interleukin (IL)-17 and IL-23. Examination of TNFAIP3 mRNA expression in skin biopsies from patients with psoriasis revealed reduced expression in both involved and uninvolved skin. Our results demonstrate the clinical importance of reduced dermal expression of A20 in psoriasis and suggest that A20 restriction of the IL-23/17 axis protects against psoriasis.

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Conflict of interest statement

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The authors (AA, MN, TK) are employed by Daiichi Sankyo Co., Ltd., but this does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Deficiency of A20 aggravates ear inflammation in an IMQ-induced psoriasis model.
(A) Thickness of IMQ or control cream white petrolatum (WP)-treated ears in male A20+/- and A20+/+ littermate mice. Results are representative of three experiments. Error bars represent SEM; N = 3 (control) or 5 (IMQ-treated) for each group,*p < 0.05 compared to IMQ-treated A20+/+ mice by Student’s t-test. (B) Appearance of inflamed ears of male A20+/- and A20+/+ littermate mice and hematoxylin and eosin (H&E)-stained sections of IMQ- or WP-treated ears in indicated genotypes at Day 8 (N = 5, 100 X magnification). (C) Histological scores of the sum of both ears on the basis of histologic findings; parakeratosis (Para), microabscess (MA), basal layer cell proliferation (BL), acanthosis (AC), and hypergranulosis (GL) are shown for male A20+/− and A20+/+ littermate mice 8 days after IMQ treatment. Scoring was performed as follows: 1, mild; 2, moderate; 3, severe. Error bars represent SEM; N = 5 for each group. *p < 0.05 compared to IMQ-treated A20+/+ mice by Wilcoxon Rank-Sum test. (D) Numbers of white blood cells (WBCs), TCRβ+TCRγδ- cells, TCRβ-TCRγδ+ cells, Gr-1-CD11b+ cells, and Gr-1+CD11b+ cells from ear-draining lymph nodes for indicated days in IMQ-treated or WP-treated male A20+/- and A20+/+ littermate mice. Results are representative of two experiments. Circles represent individual data, and horizontal bars represent the mean of each group. N = 3 or 4 for each group, *p < 0.05 compared to IMQ-treated A20+/+ mice by Student’s t-test.
Fig 2
Fig 2. A20 restricts psoriasis-related inflammatory cells responses by TLR7/8 stimulation.
(A) Cytokine concentration in ears of male A20+/- and A20+/+ littermate mice treated with WP or IMQ for 3 or 8 consecutive days. Circles represent individual data, and horizontal bars represent the mean for each group. N = 3 or 4 for each group, *p < 0.05 compared to IMQ-treated A20+/+ mice by Student’s t-test (B) Time course of cytokine production in splenocytes stimulated with IMQ (1 μg/mL). Splenocytes were obtained from non-treated male A20+/- and A20+/+ littermate mice, stimulated with IMQ for the indicated time, and the produced cytokines in the culture supernatant were mesured. Data are representative of two experiments. Error bars represent SEM; N = 3 for each group, *p < 0.05 compared to cytokine production in A20+/+ splenocytes by Student’s t-test.
Fig 3
Fig 3. Effect of neutralization of IL-17 or IL-23 to ear inflammation in IMQ-treated A20 knockout mice.
Thickness of IMQ- treated ears of male A20+/- and A20+/+ littermate mice with 100 μg/body anti-IL-17 antibody, anti-IL-12p40 antibody, or control IgG2A antibody (R&D Systems) after 6 consecutive days. Antibodies were administrated by intravenous injection the day before the IMQ treatment. Error bars represent SEM; N = 3 or 4 for each group, #p < 0.05 compared to IMQ- and control IgG2A-treated A20+/+ mice and *p < 0.05 compared to IMQ- and anti-IL-17 antibody-treated A20+/- mice by Student’s t-test.
Fig 4
Fig 4. A20 restricts interleukin (IL)-23 signal to IL-17 producing cells.
(A) Thickness of IL-23- or BSA-treated ears in A20+/- and A20+/+ littermate mice. Data are representative of two experiments. Error bars represent SEM; N = 3 (male, BSA injected group) or 9 (1 male and 8 female of A20+/- mice, and 2 male and 7 female of A20+/+ mice for IL-23-injected group) for each group,*p < 0.05 compared to IL-23-treated A20+/+ mice by Student’s t-test. (B) Numbers of TCRγδ+, TCRαβ+, IL-17+ TCRγδ+, and IL-17+ TCRαβ+ T cells from ear-draining lymph nodes from IL-23-treated or BSA-treated mice of indicated genotypes. Data are representative of two experiments. Error bars represent SEM; N = 3 (male, BSA-injected group) or 9 (1 male and 8 female of A20+/- mice, and 2 male and 7 female of A20+/+ mice for IL-23-injected group) for each group, *p < 0.05 compared to IL-23-treated A20+/+ mice by Student’s t-test.
Fig 5
Fig 5. Gene expression of TNFAIP3, IL17A, IL12p40 and TNFα in psoriasis skin specimens in both non-lesional and lesional tissues.
Data are obtained from GEO. DataSet type: expression profiling by array, transformed count, 82 samples, *p < 0.05 compared to normal skin of healthy controls and #p < 0.05 compared to uninvolved skin of patients with psoriasis by Steel’s test.
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