Expression data from mouse adult epidermis in response to physical or immune mediated damage. Mus musculus

Whether epidermal factors play a primary role in immune-mediated skin diseases such as psoriasis is unknown. We now show that the pro-differentiation transcription factor Grainyhead-like 3 (GRHL3), essential during epidermal development but dispensable in adult skin homeostasis, is required for barrier repair after adult epidermal injury. Consistent with activation of a GRHL3-regulated repair pathway in psoriasis, we find GRHL3 up-regulation in lesional skin where GRHL3 binds known epidermal differentiation gene targets. Furthermore, we show the functionality of this pathway in the Imiquimod mouse model of immune-mediated epidermal hyperplasia where loss of Grhl3 exacerbates the epidermal damage response, conferring greater sensitivity to disease induction, delayed resolution of epidermal lesions, and resistance to anti-IL-22 therapy. ChIP-seq and gene expression profiling studies show that while GRHL3 regulates differentiation genes both in development and during repair from immune-mediated damage, it targets distinct sets of genes in the two processes. In particular, GRHL3 suppresses a number of alarmin and other pro-inflammatory 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. Overall design: A single timepoint was assessed after physical injury of the epidermal barrier and two timepoints were assessed after immune mediated injury of the epidermis following Imiquimod treatment (psoriasis mouse model)