Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation
Eleftheria Papaioannou, … , Ryan F. L. O’Shaughnessy, Tessa Crompton
Eleftheria Papaioannou, … , Ryan F. L. O’Shaughnessy, Tessa Crompton
Published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3153-3170. https://doi.org/10.1172/JCI125170.
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Research Article Immunology Inflammation

Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation

Abstract

Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor–β (TGF-β) in Treg signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4+ T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4+ T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven, Treg cell–mediated immune suppression, paving the way for a potential new therapeutic strategy.

Authors

Eleftheria Papaioannou, Diana C. Yánez, Susan Ross, Ching-In Lau, Anisha Solanki, Mira Manilal Chawda, Alex Virasami, Ismael Ranz, Masahiro Ono, Ryan F. L. O’Shaughnessy, Tessa Crompton

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Figure 4

Exacerbated skin inflammation on induction of AD when Hh pathway activation in T cells is inhibited.

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Exacerbated skin inflammation on induction of AD when Hh pathway activat...
AD was induced in WT (black) and Gli2ΔC2 (red) mice by Oxa treatment. (A) Mean ± SEM ear thickness from Oxa-treated WT and Gli2ΔC2 mice on days 5 to 14 after initiation of Oxa treatment. (B) Representative H&E images of skin sections from untreated (baseline) and Oxa-treated WT and Gli2ΔC2 (day 14) mice. Scale bar: 100 μm. Plots show dermal (upper) and epidermal (lower) thickness for control and Oxa-treated groups (day 14); 2-way ANOVA. (C) Shh, Filaggrin, Il4, and Il13 expression (QRT-PCR) in ear homogenates from Oxa-treated WT and Gli2ΔC2 mice. Data from 2 independent experiments. (D) Cytokine concentration in skin supernatants from untreated and Oxa-treated WT and Gli2ΔC2 mice. Data from 2 independent experiments, analyzed by 2-way ANOVA. (E–G) Data from 2 independent experiments with at least 6 mice per group. (E) Percentage and number from ear of skin CD4+ and CD8+ T cells from Oxa-treated WT and Gli2ΔC2 mice. (F) Percentage of skin CD4+ T cells that express cytokines in Oxa-treated WT and Gli2ΔC2 mice. (G) Percentage of skin CD8+ T cells that express IFN-γ and IL-17. Two-tailed unpaired Student’s t test; 2-way ANOVA (B, D). Plots are mean ± SEM; each symbol represents an individual animal. *P < 0.05, **P < 0.01, ***P < 0.001.