期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 12, 页码 5205-5218出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI77138
关键词
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资金
- NIH [AR44882, T32-HD60555, 1F32AR065356-01A1, K08AR060802, LM010235, NLM T15 LM07443]
- Irving Weinstein Foundation
- National Psoriasis Foundation
- A. Alfred Taubman Medical Research Institute (via the Frances and Kenneth Eisenberg Emerging Scholar Award)
- Doris Duke Foundation
- American Skin Association Carson Family Research Scholar Award in Psoriasis
- NSF [IIS-0513376]
- UCI Institute for Clinical and Translational Science [UL1 TR000153]
- UCI Institute for Genomics and Bioinformatics
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.
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