S100A7 (psoriasin) inhibits human epidermal differentiation by enhanced IL‐6 secretion through IκB/NF‐κB signalling

Abstract

Psoriasin (S100A7), a member of the S100 protein family, is a well-known antimicrobial peptide and a signalling molecule which regulates cellular function and is highly expressed in hyperproliferative skin conditions such as atopic dermatitis (AD) and psoriasis with disrupted skin barrier function. However, its role in epidermal differentiation remains unknown. We examined the effect of S100A7 on epidermal differentiation in normal human keratinocytes (NHKs) and on a reconstituted human epidermis model. When NHKs were exposed to disruptive stimuli such as Staphylococcus aureus, ultraviolet irradiation and retinoic acid, the secretion of S100A7 into the culture medium increased and the expression of epidermal differentiation markers decreased. Treatment of NHKs with S100A7 significantly inhibited epidermal differentiation by reducing the expression of keratin 1, keratin 10, involucrin and loricrin and by increasing the expression of abnormal differentiation markers (keratin 6 and keratin 16). We verified that the MyD88-IκB/NF-κB signal cascade was activated via RAGE after S100A7 treatment, resulting in the upregulation of interleukin-6. Finally, we confirmed that S100A7 is a negative regulator of epidermal differentiation using a reconstituted human epidermis model. This study suggests that S100A7-related signalling molecules could be potent targets for recovering skin barrier function in AD and psoriasis where S100A7 is accumulated excessively.

Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

“…Members of the S100 protein family (S100A7, S100A8 and S100A9) function as AMPs, as well as damage-associated molecular pattern molecules, which have proinflammatory activities. The levels of S100 proteins are increased in patients with acute and chronic AD, and their proinflammatory properties may result in defects of epidermal differentiation and cutaneous inflammation [113,114]. …”

“…Similar to Th2 cytokines, IL-22 compromises the epidermal barrier by suppressing major terminal differentiation proteins [135]. IL-22 increases S100A7, S100A8 and S100A9 gene expression, thus inhibiting epidermal differentiation by enhancing IL-6 secretion, and exerts a proinflammatory effect in AD lesions [114,121]. IL-22 and IL-17 synergistically increase the levels of S100 proteins and AMPs in the epidermis [12,136].…”

Epidermal CD147 expression plays a key role in IL-22-induced psoriatic dermatitis

“…S100A family members are calcium-binding proteins produced by keratinocytes that protect the skin from microorganisms4041 and exert pro-inflammatory effects based on the chemotactic effects of neutrophils and CD4(+) cells4243. S100A family member expression levels are increased in psoriatic skin lesions404144.…”

Implicações Terapêuticas dos Novos Conhecimentos Sobre a Fisiopatologia da Dermite Atópica

“…22,24 Tal como as IL-4 e IL-13, também a IL-22 tem sido implicada na disfunção da barreira cutânea e hiperplasia epidér-mica. [25][26][27] Fezakinumab é um anticorpo anti IL-22 desenhado para a psoríase e artrite reumatóide mas cujo estudo de fase II para a artrite reumatóide foi abandonado em 2011.…”