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 3

Pharmacological Smo inhibition exacerbates AD in WT mice.

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Pharmacological Smo inhibition exacerbates AD in WT mice. Data from 2 in...
Data from 2 independent experiments with 7 Oxa-treated WT mice per group unless otherwise stated. Control (black, DMSO-only–injected) and Smo-inh–injected (red) mice; each symbol represents an individual animal. (A) Scheme of Oxa administration with i.p. Smo-inh or DMSO injection. (B) Plot shows ear thickness from Oxa-treated control and Smo-inh–injected groups. (C) Representative H&E images of ear sections from Oxa-treated WT mice injected either with DMSO only (left image) or Smo-inh (right) at termination (day 14). Scale bar: 100 μm. Plots show dermal and epidermal thickness of Oxa-treated WT without Smo-inh (DMSO-only control) and with Smo-inh on day 14. (D) Serum IgE concentration from Oxa-treated control and Smo-inh–injected mice measured by ELISA. (E) Shh expression (QRT-PCR) in whole ear homogenates from Oxa-treated and Oxa-untreated mice without Smo-inh injection (DMSO-only control) and with Smo-inh injection. (F) Percentage and number of skin leukocytes (CD45+), macrophages (Mϕ; CD45+CD11b+F4/80+) and eosinophils (Eos; CD45+CD11b+SiglecF+) from ear skin from Oxa-treated control (DMSO only) and Smo-inh–injected mice. (G) Percentage of skin CD4+ T cells that expressed IFN-γ and IL-17 from Oxa-treated control (DMSO only) and Smo-inh–injected mice. (H) Percentage of skin CD8+ T cells that expressed IFN-γ and IL-17 from Oxa-treated control (without Smo-inh, DMSO only) and Smo-inh–injected mice. (I) Percentage of skin CD4+ T cells that are Treg (CD3+CD25+icFoxp3+) from Oxa-treated control (without Smo-inh, DMSO only) and Smo-inh–injected mice. Plots are mean ± SEM; 2-tailed unpaired Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001.