DLX3-dependent STAT3 signaling in keratinocytes regulates skin immune homeostasis

Title
DLX3-dependent STAT3 signaling in keratinocytes regulates skin immune homeostasis
Authors
김진철Gaku NakatoVeronica NagleStephen R. BrooksMark C. UdeyMaria I. MorassoShreya BhattacharyaYouichi Ogawa
Issue Date
2018-05
Publisher
The Journal of investigative dermatology
Citation
VOL 138-1061
Abstract
Epidermal-specific deletion of the homeobox transcription regulator DLX3 disrupts keratinocyte differentiation and results in an IL-17linked 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-17Asecreting Vg4 gd 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 signalingrelated 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.
URI
http://pubs.kist.re.kr/handle/201004/70209
ISSN
0022-202X
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KIST Publication > Article
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