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.

Activation of NLRP3 signalling accelerates skin wound healing

“…S100a8 is an inflammatory marker in various diseases. A recent study demonstrated that S100A8 deficiency impaired keratinocyte migration and proliferation . In the present study, IL‐6, TNF‐α, CCL2 and s100a8 mRNA expression was downregulated in the wound site of NALP3‐KO mice.…”

Imiquimod‐induced skin inflammation is relieved by knockdown of sodium channel Nax

“…S100A9, which is a downstream gene of Na x , functions as a pro‐inflammatory cytokine in the epidermis . We observed that S100A9 is highly expressed in the epidermis of human hypertrophic scars and keloid tissues in which the barrier function of the skin is impaired . Increased expression of S100A9 has also been detected in psoriatic skin lesions .…”

“…We previously showed that Na x controls pro‐inflammatory signalling in the epidermis . S100A9, which is a downstream gene of Na x , functions as a pro‐inflammatory cytokine in the epidermis . We observed that S100A9 is highly expressed in the epidermis of human hypertrophic scars and keloid tissues in which the barrier function of the skin is impaired .…”

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

“…The knockdown of keratinocyte S100A8 , recently shown to be upregulated in both keloid and hypertrophic scar epidermis, resulted in a failure to activate co-cultured fibroblasts and reduction in dermal fibrosis [48]. As a mediator of neutrophil migration [49, 50], S100A8 is found in the supra-basal epidermis following injury, but gradually returns to baseline in a normally healed wound [51].…”