The expression of proinflammatory genes in epidermal keratinocytes is regulated by hydration status.
Mucosal wounds heal more rapidly, exhibit less inflammation, and are associated with minimal scarring when compared with equivalent cutaneous wounds. We previously demonstrated that cutaneous epithelium exhibits an exaggerated response to injury compared with mucosal epithelium. We hypothesized that treatment of injured skin with a semiocclusive dressing preserves the hydration of the skin and results in a wound healing phenotype that more closely resembles that of mucosa. Here we explored whether changes in hydration status alter epidermal gene expression patterns in rabbit partial-thickness incisional wounds. Using microarray studies on injured epidermis, we showed that global gene expression patterns in highly occluded versus non-occluded wounds are distinct. Many genes including IL-1β, IL-8, TNF-α (tumor necrosis factor-α), and COX-2 (cyclooxygenase 2) are upregulated in non-occluded wounds compared with highly occluded wounds. In addition, decreased levels of hydration resulted in an increased expression of proinflammatory genes in human ex vivo skin culture (HESC) and stratified keratinocytes. Hierarchical analysis of genes using RNA interference showed that both TNF-α and IL-1β regulate the expression of IL-8 through independent pathways in response to reduced hydration. Furthermore, both gene knockdown and pharmacological inhibition studies showed that COX-2 mediates the TNF-α/IL-8 pathway by increasing the production of prostaglandin E2 (PGE2). IL-8 in turn controls the production of matrix metalloproteinase-9 in keratinocytes. Our data show that hydration status directly affects the expression of inflammatory signaling in the epidermis. The identification of genes involved in the epithelial hydration pathway provides an opportunity to develop strategies to reduce scarring and optimize wound healing.
Laboratory for Wound Repair and Regenerative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Wei
W
Xu
Laboratory for Wound Repair and Regenerative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Shengxian
S
Jia
Laboratory for Wound Repair and Regenerative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Ping
P
Xie
Laboratory for Wound Repair and Regenerative Medicine, 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.
Aimei
A
Zhong
Laboratory for Wound Repair and Regenerative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Robert D
RD
Galiano
Laboratory for Wound Repair and Regenerative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: tmustoe@nmh.org.
Thomas A
TA
Mustoe
Laboratory for Wound Repair and Regenerative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: seok-hong@northwestern.edu.
Seok J
SJ
Hong
D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009092:Mucous Membrane / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014867:Water / Q000378:metabolism; D014945:Wound Healing
D053583:Interleukin-1beta; D016209:Interleukin-8; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D014867:Water; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone