Deletion of S100a8 and S100a9 Enhances Skin Hyperplasia and Promotes the Th17 Response in Imiquimod-Induced Psoriasis

Abstract

High concentrations of the damage-associated molecular patterns S100A8 and S100A9 are found in skin and serum from patients suffering from psoriasis, an IL-17–related disease. Notably, although the expression of these proteins correlates with psoriatic disease severity, the exact function of S100A8 and S100A9 in psoriasis pathogenesis remains unclear. In this study, we investigated the role of S100A8 and S100A9 in psoriasis-associated skin hyperplasia and immune responses using S100a8−/− and S100a9−/− mice in an imiquimod-induced model of psoriasis. We found that S100a8−/− and S100a9−/− psoriatic mice exhibit worsened clinical symptoms relative to wild-type mice and increased expression of S100A9 and S100A8 proteins in keratinocytes, respectively. In addition, the loss of S100A8 enhances proliferation of keratinocytes and disrupts keratinocyte differentiation. We further detected elevated production of IL-17A and -F from CD4+ T cells in the absence of S100A8 and S100A9, as well as increased infiltration of neutrophils in the skin. In addition, treatment with anti–IL-17A and -F was found to reduce psoriasis symptoms and skin hyperplasia in S100a8−/− and S100a9−/− mice. These data suggest that S100A8 and S100A9 regulate psoriasis by inhibiting production of IL-17A and -F, thereby, to our knowledge, providing new insights into their biological functions.

S100A8 and S100A9, both transcriptionally regulated by PU.1, promote epithelial-mesenchymal transformation (EMT) and invasive growth of dermal keratinocytes during scar formation post burn

“…Several recent studies revealed that S100A8 and S100A9 are also expressed in fibroblasts, keratinocytes, and other cell components of the skin. S100A8 and S100A9 were robustly upregulated in skin tissues under pathological conditions, such as psoriasis, atopic dermatitis, and wounds, and they contributed to development of these pathological processes [10][11][12]. In wounded skins, S100A8 and S100A9 expression were induced to promote fibroblast activation and dermal fibrosis.…”

Goeckerman Regimen Reduces Alarmin Levels and PASI Score in Paediatric Patients with Psoriasis

“…In the mice imiquimod-induced psoriasis model, the abrogated activity of extracellular S100A8 and S100A9 increased PASI and elevated the production of IL-17. Additionally, S100A8 regulated differentiation and inhibited proliferation of keratinocytes; thus, prevented the development of skin hyperplasia (53). An almost unchanged level of S100A8 in our study might have had an ameliorating effect on the severity of psoriasis and might slightly reduce the level of IL-17.…”

Single-Cell Transcriptomics Uncover Key Regulators of Skin Regeneration in Human Long-Term Mechanical Stretch-Mediated Expansion Therapy

“…IF analysis confirmed significant upregulation of Amphiregulin (AREG) and SERPINB2 in Exp vs. Nby comparison at the protein level ( Figure 5D ). Notably, S100A8 , the downregulated gene, was the damage-associated molecular in skin disorders and will be secreted under inflammatory microenvironment ( Defrêne et al, 2021 ). Its downregulation suggested the degree of inflammatory response was attenuated over time.…”