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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

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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 1

Shh upregulation and in vivo activation of the Hh signaling pathway upon induction of AD.

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Shh upregulation and in vivo activation of the Hh signaling pathway upon...
Black circles, control mice; red squares, Oxa-treated mice. Each symbol represents an individual animal. (A) Sensitization and challenge scheme of Oxa treatment. (B) mRNA expression by QRT-PCR of Hh signaling components in whole ear skin homogenates from untreated WT and Oxa-treated WT mice. Data from 2 independent experiments. (C) Representative immunofluorescence staining images of Shh (red) expression in frozen skin sections from untreated WT (day 0) and Oxa-treated WT mice on days 6, 8, 10, 12, and 14 after initiation of the Oxa protocol. DAPI-stained nuclei are shown in blue. Scale bar: 100 μm (n = 5 mice per group). (D) Time course of ear thickness from Rag1-KO control (blue), Oxa-treated Rag1-KO (green), WT control (black), and Oxa-treated WT (red) mice (n = 6 per group). (E) Representative immunofluorescence staining images of Shh (red) expression in frozen skin sections from untreated Rag1-KO and Oxa-treated Rag1-KO mice on termination (day 14). DAPI-stained nuclei are in blue. Scale bar: 100 μm (n = 3 mice per group). Plot shows comparison of Shh mRNA expression in whole ear homogenates from control untreated Rag1-KO (n = 3) and Oxa-treated Rag1-KO (n = 3) with equivalent Shh expression data from WT from B. Data from 2 independent experiments. (F) Representative density plots of GFP expression in skin CD3+ T cells from untreated and Oxa-treated GBS-GFP transgenic mice, giving percentage of cells in GFP+ region shown. Plots show number of skin GFP+CD4+ and GFP+CD8+ T cells isolated from ears from untreated and Oxa-treated GBS-GFP transgenic mice. (G) MFI of GFP in skin GFP+CD4+ and GFP+CD8+ T cells from untreated and Oxa-treated GBS-GFP transgenic mice. In B, E–G, 2-tailed unpaired Student’s t test was used; in D, ANOVA was used. Plots show mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
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