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A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia
William M. Gordon, … , Pierre F. Baldi, Bogi Andersen
William M. Gordon, … , Pierre F. Baldi, Bogi Andersen
Published December 1, 2014; First published October 27, 2014
Citation Information: J Clin Invest. 2014;124(12):5205-5218. https://doi.org/10.1172/JCI77138.
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Categories: Research Article Dermatology

A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

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Abstract

Dermal infiltration of T cells is an important step in the onset and progression of immune-mediated skin diseases such as psoriasis; however, it is not known whether epidermal factors play a primary role in the development of these diseases. Here, we determined that the prodifferentiation transcription factor grainyhead-like 3 (GRHL3), which is essential during epidermal development, is dispensable for adult skin homeostasis, but required for barrier repair after adult epidermal injury. Consistent with activation of a GRHL3-regulated repair pathway in psoriasis, we found that GRHL3 is upregulated in lesional skin and binds known epidermal differentiation gene targets. Using an imiquimod-induced model of immune-mediated epidermal hyperplasia, we found that mice lacking GRHL3 have an exacerbated epidermal damage response, greater sensitivity to disease induction, delayed resolution of epidermal lesions, and resistance to anti–IL-22 therapy compared with WT animals. ChIP-Seq and gene expression profiling of murine skin revealed that while GRHL3 regulates differentiation pathways both during development and during repair from immune-mediated damage, it targets distinct sets of genes in the 2 processes. In particular, GRHL3 suppressed a number of alarmin and other proinflammatory genes after immune injury. This study identifies a GRHL3-regulated epidermal barrier repair pathway that suppresses disease initiation and helps resolve existing lesions in immune-mediated epidermal hyperplasia.

Authors

William M. Gordon, Michael D. Zeller, Rachel H. Klein, William R. Swindell, Hsiang Ho, Francisco Espetia, Johann E. Gudjonsson, Pierre F. Baldi, Bogi Andersen

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Figure 1

Grhl3 is dispensable for epidermal differentiation in the adult mouse, but is required for resolution of epidermal injury.

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Grhl3 is dispensable for epidermal differentiation in the adult mouse, b...
(A) Toluidine blue staining of WT (n = 2) and Grhl3 cKO (Krt14-Cre Grhl3fl/fl; n = 2) skin at the indicated postnatal days. Dashed red line denotes basal lamina separating epidermis (Epi) from dermis (Drm). Original magnification, ×1,000. (B) Grhl3 mRNA expression, by quantitative PCR, in WT skin during embryonic development and postnatally (n = 3 mice per time point). (C) β-Gal IHC in Grhl3-Cre/LacZ reporter mice at P0 and P56. Dashed red line denotes basal lamina. Original magnification, ×400. (D) Nonhealing abrasive injury (received 3 months earlier) in a Grhl3 cKO mouse. (E) H&E staining of unaffected and affected regions of Grhl3 cKO skin 3 months after injury. Hair follicles (HF) are indicated. Original magnification, ×100. (F) KRT6 IHC in the affected area of a Grhl3 cKO nonhealing abrasive injury. Original magnification, ×100 (top); ×400 (bottom).
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