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 October 27, 2014
Citation Information: J Clin Invest. 2014;124(12):5205-5218. https://doi.org/10.1172/JCI77138.
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Research Article Dermatology

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

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 3

A GRHL3-regulated epidermal repair pathway in human psoriasis.

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A GRHL3-regulated epidermal repair pathway in human psoriasis. (A) Relat...
(A) Relative GRHL3 mRNA expression in normal (NN), uninvolved (PN), and psoriatic lesions (PP) from published datasets (31–33). (B) GRHL3 expression in individuals from 3 independent experiments (refs. 31–33; N for each dataset indicated within graph). (C) Top Spearman correlations of GRHL3 expression to cytokine gene signatures (75) in lesional psoriasis. ***P < 0.001. (D) Overlap of DEGs in GRHL3 knockdown (KD) human keratinocytes with DEGs in human psoriatic lesions versus uninvolved skin. (E) Overlap of DEGs in common in D and the GRHL3 human keratinocyte (KC) ChIP-Seq peaks (+10 to –5 kb of TSS). (F) GRHL3 binding (ChIP-PCR) to the indicated gene targets in normal and lesional psoriasis skin. (G–I) Examples of GRHL3-regulated genes in psoriasis lesional skin that, based on the GRHL3 RNAi experiments in human keratinocytes, were regulated in the expected manner (G), opposite the expected manner (H), or unchanged (I) compared with normal skin. Red arrows, predicted upregulation; green arrows, predicted downregulation. (A and G–I) Boxes denote IQR, lines denote median, upper whiskers denote lesser of either (quartile 3 + 1.5×IQR) or maximum value, lower whiskers denote greater of either (quartile 1 – 1.5×IQR) or minimum value.