S100A8 and S100A9-mediated keratinocyte affecting T lymphocyte immune imbalance through TLR4/NF-κ B in psoriasis.

Psoriasis is a chronic,immune-mediated inflammatory skin disorder characterized by recurrent thick plaque. As an alarmin of inflammation, the importance of S100A8 and S100A9 have already been confirmed to be associated with the development of chronic inflammation in diseases. However, the precise mechanisms of S100A8 and S100A9 in psoriasis remain unclear. Therefore,the aim of this study was to elucidate the effects and underlying mechanisms of S100A8 and S100A9 in psoriasis. In this study, we found that both S100A8 and S100A9 were highly expressed in cells treated with M5-a cytokine mixture containing IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α-as well as in a mouse model of imiquimod (IMQ)-induced psoriasis. Meanwhile, S100A8 and S100A9 knockdown in normal human epidermal keratinocytes (NHEK) inhibited the proliferation of NHEK cells in psoriasis. To further investigate the effects of S100A8 and S100A9 on psoriatic inflammation, T cells were co-cultured with S100A8 and S100A9 knockdown NHEK cells, and S100A8 and S100A9 promoted the production of pro-inflammatory cytokines by T cells through activation of Toll-like receptor 4 (TLR4)/NF-κB signaling pathway. In particular, when the S100A8 and S100A9 inhibitor paquinimod was added to a mouse model of imiquimot-induced psoriasis, psoriatic dermatitis and inflammatory factors were reduced, and the expression of TLR4/NF-κB was also significantly reduced. In conclusion, this study illustrated that S100A8 and S100A9 participates in the pathogenesis of psoriasis by activating TLR4/NF-κB signaling pathways, thereby promoting psoriasis-associated skin inflammation, which suggested the potential role of S100A8 and S100A9 in the development of psoriasis and provided new insight into targeted therapies.