WNT5A drives interleukin-6-dependent epithelial–mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis
- Burns & Trauma Vol. 10, Issue 1, (2022)
- 作者机构：
Yonsei University College of Medicine
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkac023
CLC：Published：2022，
Published Online：7 October 2022，
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Young In Lee, Jung Eun Shim, Jihee Kim, Won Jai Lee, Jae Woo Kim, Kee Hyun Nam, Ju Hee Lee, WNT5A drives interleukin-6-dependent epithelial–mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis, Burns & Trauma, Volume 10, 2022, tkac023, https://doi.org/10.1093/burnst/tkac023
Young In Lee, Jung Eun Shim, Jihee Kim, Won Jai Lee, Jae Woo Kim, Kee Hyun Nam, Ju Hee Lee, WNT5A drives interleukin-6-dependent epithelial–mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis, Burns & Trauma, Volume 10, 2022, tkac023, https://doi.org/10.1093/burnst/tkac023 DOI：
摘要
Abstract
BackgroundKeloid scarring is a fibroproliferative disease caused by aberrant genetic activation with an unclear underlying mechanism. Genetic predisposition
aberrant cellular responses to environmental factors
increased inflammatory cytokines and epithelial–mesenchymal transition (EMT) phenomena are known as major contributors. In this study
we aimed to identify the molecular drivers that initiate keloid pathogenesis.MethodsBulk tissue RNA sequencing analyses of keloid and normal tissues along with ex vivo and in vitro tests were performed to identify the contributing genes to keloid pathogenesis. An animal model of inflammatory keloid scarring was reproduced by replication of a skin fibrosis model with intradermal bleomycin injection in C57BL/6 mice.ResultsGene set enrichment analysis revealed upregulation of Wnt family member 5A (WNT5A) expression and genes associated with EMT in keloid tissues. Consistently
human keloid tissues and the bleomycin-induced skin fibrosis animal model showed significantly increased expression of WNT5A and EMT markers. Increased activation of the interleukin (IL)-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and subsequent elevation of EMT markers was also observed in keratinocytes co-cultured with WNT5A-activated fibroblasts or keloid fibroblasts. Furthermore
WNT5A silencing and the blockage of IL-6 secretion via neutralizing IL-6 antibody reversed hyperactivation of the STAT pathway and EMT markers in keratinocytes. Lastly
STAT3 silencing significantly reduced the EMT-like phenotypes in both keratinocytes and IL-6-stimulated keratinocytes.ConclusionsIntercellular communication via the WNT5A and STAT pathways possibly underlies a partial mechanism of EMT-like phenomena in keloid pathogenesis. IL-6 secreted from WNT5A-activated fibroblasts or keloid fibroblasts activates the JAK/STAT signaling pathway in adjacent keratinocytes which in turn express EMT markers. A better understanding of keloid development and the role of WNT5A in EMT will promote the development of next-generation targeted treatments for keloid scars.
关键词
Keywords
KeloidWnt family member 5AInterleukin-6JAK/STAT pathwayEpithelial–mesenchymal transitionScar Epithelial mesenchymal transition
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