title: 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.forename: William M
authors.initials: WM
authors.lastname: Gordon
authors.forename: Michael D
authors.initials: MD
authors.lastname: Zeller
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Klein
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.forename: Hsiang
authors.initials: H
authors.lastname: Ho
authors.forename: Francisco
authors.initials: F
authors.lastname: Espetia
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Baldi
authors.forename: Bogi
authors.initials: B
authors.lastname: Andersen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D017573:Focal Epithelial Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C499942:Grhl3 protein, mouse; D014157:Transcription Factors