The Expression of Proinflammatory Genes in Epidermal Keratinocytes Is Regulated by Hydration Status

Abstract

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.

Increased epidermal thickness and abnormal epidermal differentiation in keloid scars

“…Decreased hydration levels, in turn, have been known to result in increased proinflammatory gene expression in epidermal keratinocytes. 53 In summary, this study lends further support to the hypothesis that keratinocytes are involved in abnormal scar formation. Yan et al 54 showed that keloid epidermal cells undergoing an epidermal-mesenchymal transition may be one of the cell types responsible for generating keloid fibroblasts.…”

“…Thus, the abnormal epidermal differentiation characterizing keloid scars may very well lead to defective CEs, with subsequent stratum corneum barrier dysfunction. Decreased hydration levels, in turn, have been known to result in increased proinflammatory gene expression in epidermal keratinocytes …”

Inflammatory microenvironment and tumor necrosis factor alpha as modulators of periostin and CCN2 expression in human non-healing skin wounds and dermal fibroblasts

“…It is possible that the abundance of TNFα staining proximal to the wound edge plays a role in dysregulation of gene expression. Recent evidence suggests that the state of hydration of the skin also has a strong effect on epithelial gene expression and TNFα is increased in wounds with less hydration [40]. Interestingly, in the regions of hyperkeratotic epithelium, TNFα staining is prominent also in the dermis, but periostin and CCN2 immunoreactivity is still present.…”

Epidermal Dysfunction Leads to an Age-Associated Increase in Levels of Serum Inflammatory Cytokines

“…Thus, increased cytokine production in aged mouse skin, which begins to demonstrate functional abnormalities by 12-month of age, likely reflects a compensatory homeostatic response to compromised permeability barrier function. In addition to a permeability barrier defect, aged skin displays low stratum corneum hydration, which likely also contributes to cutaneous inflammation, because reductions in stratum corneum hydration alone increase cutaneous cytokine expression (Denda et al, 1998), while conversely improvements in stratum corneum hydration relieve cutaneous inflammation (Kikuchi et al, 2003; Xu et al, 2014). Therefore, increased levels of epidermal cytokines likely result from both the compromised permeability barrier function and reduced stratum corneum hydration levels in aged skin.…”