DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis

Shreya Bhattacharya, Jin Chul Kim, Youichi Ogawa, Gaku Nakato, Veronica Nagle, Stephen R. Brooks, Mark C. Udey, Maria I. Morasso

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Epidermal-specific deletion of the homeobox transcription regulator DLX3 disrupts keratinocyte differentiation and results in an IL-17−linked psoriasis-like skin inflammation. To identify the epidermal initiating signals produced by DLX3-null keratinocytes, we performed acute deletion of DLX3 in adult epidermis using a tamoxifen-inducible Krt14-cre/ERT system. K14CreERT;DLX3fl/fl skin exhibited dysregulated expression of differentiation-associated genes, upregulation of proinflammatory cytokines, and accumulation of Langerhans cells and macrophages within 3 days of tamoxifen-induced DLX3 ablation. We also observed increased accumulation of IL-17A−secreting Vγ4 γδ T cells and heightened levels of IL-17 and IL-36 family of cytokines starting 1 week after DLX3 deletion. Interestingly, transcriptome profiling of K14CreERT;DLX3fl/fl epidermis at 3 days identified activated STAT3 as a transcriptional regulator and revealed differential expression of STAT3 signaling-related genes. Furthermore, activation of STAT3 was strongly increased in K14CreERT;DLX3fl/fl skin, and topical treatment with an inhibitor of STAT3 activation attenuated the immune phenotype. RNA-seq analysis of vehicle and STAT3 inhibitor treated K14CreERT;DLX3fl/fl skin identified differentially expressed genes associated with inhibition of leukocyte infiltration. Collectively, our results show that DLX3 is a critical regulator of STAT3 signaling network that maintains skin homeostasis.

Original languageEnglish
Pages (from-to)1052-1061
Number of pages10
JournalJournal of Investigative Dermatology
Volume138
Issue number5
DOIs
StatePublished - May 2018

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    Bhattacharya, S., Kim, J. C., Ogawa, Y., Nakato, G., Nagle, V., Brooks, S. R., Udey, M. C., & Morasso, M. I. (2018). DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis. Journal of Investigative Dermatology, 138(5), 1052-1061. https://doi.org/10.1016/j.jid.2017.11.033