Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation
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
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
View: Text | PDF
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

×

Figure 2

Shh mutation aggravates but Gli3 mutation ameliorates chronic AD.

Options: View larger image (or click on image) Download as PowerPoint
Shh mutation aggravates but Gli3 mutation ameliorates chronic AD. (A–F) ...
(A–F) Oxa-treated Shh+/– mice (red) and WT littermates (black). (A) Shh expression (QRT-PCR) in ear homogenates from Oxa-treated WT and Shh+/– mice. (B) Representative H&E images of ear sections from Oxa-treated WT (n = 4) and Shh+/– (n = 4) mice (day 14), showing areas of hyperkeratosis (green arrows) and parakeratosis (white arrows). Scale bar: 100 μm. Plots show dermal and epidermal thickness. (C) Serum IgE concentration (ELISA) from Oxa-treated WT and Shh+/– mice. (D) Il4 and Il13 expression (QRT-PCR) in whole ear homogenates from Oxa-treated WT and Shh+/– mice. (E) Contour plot shows CD4 and CD8 expression, gated on CD45+CD3+γδTCR– cells from ears of Oxa-treated WT and Shh+/– mice. Plots show number of CD4+ and CD8+ T cells isolated from ears. (F) Percentage of skin T cells from Oxa-treated WT and Shh+/– mice that express IFN-γ, IL-4, IL-13, and IL-17, measured by flow cytometry. (G) Shh expression (QRT-PCR) in whole ear homogenates from untreated WT (black) and Gli3+/– (red) mice. (H–L) Data from 2 independent experiments using Oxa-treated WT (black) and Gli3+/– (red) littermates. (H) Representative H&E images of ear sections from untreated (baseline) and Oxa-treated WT and Gli3+/– mice (day 14), showing areas of hyperkeratosis (green arrows) and parakeratosis (white arrows). Scale bar: 100 μm. Plots show dermal and epidermal thickness. (I) Serum IgE concentration (ELISA) from Oxa-treated WT and Gli3+/– mice. (J) Il4, Il13, and Shh expression (QRT-PCR) in whole ear homogenates from Oxa-treated WT and Gli3+/– mice. (K) Contour plot shows CD4 and CD8 expression, gated on CD45+CD3+γδTCR– cells isolated from Oxa-treated ears from WT and Gli3+/– mice. Plots show number of CD4+ and CD8+ T cells isolated from ears. (L) Percentage of skin T cells from Oxa-treated WT and Gli3+/– mice that express IFN-γ, IL-4, IL-13, and IL-17, measured by flow cytometry. Plots show mean ± SEM; each symbol represents an individual animal; 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.