Epidermal HMGB1 Activates Dermal Fibroblasts and Causes Hypertrophic Scar Formation in Reduced Hydration
Autor: | Wu Jun, Qiyi Zhai, Jingling Zhao, Jian-Xing Yu, Shaohai Qi, Yingbin Xu, Bin Shu, Fei Zhou, Lei Chen |
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Rok vydání: | 2018 |
Předmět: |
Keratinocytes
0301 basic medicine Cicatrix Hypertrophic medicine.medical_treatment Active Transport Cell Nucleus Organism Hydration Status chemical and pharmacologic phenomena Dermatology HMGB1 Biochemistry 03 medical and health sciences Hypertrophic scar Glycation Fibrosis medicine Animals Humans HMGB1 Protein Promoter Regions Genetic Receptor Fibroblast Molecular Biology Cells Cultured Wound Healing biology Chemistry Cell Biology Fibroblasts medicine.disease Actins Coculture Techniques Cell biology Disease Models Animal 030104 developmental biology Cytokine medicine.anatomical_structure Trans-Activators biology.protein Rabbits Epidermis Wound healing |
Zdroj: | Journal of Investigative Dermatology. 138:2322-2332 |
ISSN: | 0022-202X |
Popis: | HMGB1 protein is a multifunctional cytokine involved in inflammatory reactions and is known to play a key role in tissue repair and fibrosis. However, the function of HMGB1 in fibrotic skin diseases, such as hypertrophic scar formation, remains unclear. In this study, HMGB1 was detected in the nuclei of epidermal cells in normal skin and had accumulated in the cytoplasm in hypertrophic scars. By establishing a keratinocyte-fibroblast co-culture and conditional medium treatment models, we found that a reduced hydration condition increased the expression and secretion of HMGB1 in keratinocytes, subsequently activating dermal fibroblasts. HMGB1 secreted from keratinocytes activated fibroblasts by promoting the nuclear import of MRTF-A, increased the nuclear accumulation of MRTF-A/SRF complexes and consequently enhanced α-smooth muscle actin promoter activation. Moreover, blockade of advanced glycation end products or Toll-like receptor 2/4 inhibited the fibroblast activation induced by HMGB1. Finally, local delivery of HMGB1 resulted in marked hypertrophic scar formation in rabbit hypertrophic scar models, while HMGB1 blockade exerted a clear anti-scarring effect. Our results indicate that high HMGB1 levels induced by a reduced hydration status play an important role in hypertrophic scar formation, strongly suggesting that HMGB1 is a novel target for preventing scarring. |
Databáze: | OpenAIRE |
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