title: S100A8 and S100A9 Are Induced by Decreased Hydration in the Epidermis and Promote Fibroblast Activation and Fibrosis in the Dermis.
abstract: The most critical function of the epidermis is to prevent water loss and maintain skin homeostasis. Disruption of the functional skin barrier causes delayed wound healing, hypertrophic scarring, and many skin diseases. Herein, we show that reduced hydration increases the expression of S100 protein family members, S100A8/S100A9, in stratified keratinocyte culture and human ex vivo skin culture. Immunohistological analyses show that S100A8/A9 are highly expressed in the epidermis of human hypertrophic scar and keloid tissues. Reduced hydration demonstrates activation of fibroblasts in the keratinocyte-fibroblast co-culture. In contrast, knockdown of S100A8 or S100A9 by RNA interference in keratinocytes failed to activate fibroblasts. Pretreatment with pharmacological blockers of S100A8/A9 receptors, Toll-like receptor 4 and receptor for advanced glycation end products, inhibits fibroblast activation induced by recombinant S100A8/A9 proteins. Moreover, we observe that local delivery of S100A8 protein results in a marked increase in hypertrophic scarring in the in vivo rabbit ear scar model. Our results indicate that hydration status promotes fibroblast activation and fibrosis by directly affecting the expression of inflammatory signaling in keratinocytes, thereby strongly suggesting S100A8/A9 to be novel targets in preventing scarring.
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; 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.
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.
authors.forename: Shengxian
authors.initials: S
authors.lastname: Jia
authors.affiliation: Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Sun
authors.affiliation: Laboratory for Wound Repair and Regenerative Surgery, Department of Surgery, Plastic Surgery Division, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
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.
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. Electronic address: seok-hong@northwestern.edu.
authors.forename: Seok J
authors.initials: SJ
authors.lastname: Hong
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D040501:Calgranulin A / Q000096:biosynthesis*; D040502:Calgranulin B / Q000096:biosynthesis*; D002921:Cicatrix / Q000378:metabolism*; D018920:Coculture Techniques; D020405:Dermis / Q000473:pathology; D004817:Epidermis / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014867:Water; D055815:Young Adult
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D014867:Water