TY - JOUR
T1 - DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis
AU - Bhattacharya, Shreya
AU - Kim, Jin Chul
AU - Ogawa, Youichi
AU - Nakato, Gaku
AU - Nagle, Veronica
AU - Brooks, Stephen R.
AU - Udey, Mark C.
AU - Morasso, Maria I.
N1 - Funding Information:
This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (M.I.M ZIA AR041124) and the Center for Cancer Research, National Cancer Institute of the National Institutes of Health. We thank members of the Laboratory of Skin Biology for helpful suggestions and discussions. We also thank Gustavo Gutierrez-Cruz, Stefania Dell’Orso, and members of the NIAMS Genome Analysis Core Facility and the NIAMS Light Imaging Core Facility.
Publisher Copyright:
© 2017 The Authors
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044778309&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2017.11.033
DO - 10.1016/j.jid.2017.11.033
M3 - Article
C2 - 29246798
AN - SCOPUS:85044778309
SN - 0022-202X
VL - 138
SP - 1052
EP - 1061
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -