title: S100A12 Induced in the Epidermis by Reduced Hydration Activates Dermal Fibroblasts and Causes Dermal Fibrosis.
abstract: Disruption of the barrier function of skin increases transepidermal water loss and up-regulates inflammatory pathways in the epidermis. Consequently, sustained expression of proinflammatory cytokines from the epidermis is associated with dermal scarring. We found increased expression of S100A12 in the epidermis of human hypertrophic and keloid scar. Exposing a stratified keratinocyte culture to a reduced-hydration environment increased the expression and secretion of S100A12 by nearly 70%, which in turn activated dermal fibroblasts in vitro. Direct treatment of fibroblasts with conditioned medium collected from stratified keratinocyte culture under reduced-hydration conditions activated fibroblasts, shown by up-regulation of α-smooth muscle actin, pro-collagen 1, and F-actin expression. However, this fibroblast activation was not found when S100A12 was knocked down by RNA interference in keratinocytes. Pharmacological blockade of S100A12 receptors, RAGE, or TLR4 inhibited S100A12-induced fibroblast activation. Local delivery of S100A12 resulted in a marked hypertrophic scar formation in a validated rabbit hypertrophic scar model compared with saline control. Our findings indicate that S100A12 functions as a proinflammatory cytokine and suggest that S100A12 is a potential therapeutic target for dermal scarring.
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jingling
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Aimei
authors.initials: A
authors.lastname: Zhong
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Friedrich
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Shengxian
authors.initials: S
authors.lastname: Jia
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Galiano
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mustoe
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery/Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: seok-hong@northwestern.edu.
authors.forename: Seok Jong
authors.initials: SJ
authors.lastname: Hong
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D017439:Cicatrix, Hypertrophic / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007249:Inflammation; D007627:Keloid / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D034622:RNA Interference; D011817:Rabbits; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D000067616:S100A12 Protein / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C000593871:AGER protein, human; D017077:Culture Media, Conditioned; D000067759:Receptor for Advanced Glycation End Products; D000067616:S100A12 Protein; C090441:S100A12 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4