Knockdown of S100A9 inhibits pyroptosis and promotes PPAR signaling pathway in atopic dermatitis

Atopic dermatitis (AD) is a common chronic and relapsing inflammatory skin disease. Although its clinical and pathological characteristics are well documented, the underlying molecular mechanisms remain incompletely elucidated.

Hub differentially expressed genes (DEGs) in AD were identified using the GSE222771 and GSE182740 datasets. Cytokine (TNF-α/IFN-γ)-stimulated HaCaT cells and 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse models were established to mimic inflammatory conditions in vitro and in vivo. Inflammatory cytokine levels and pyroptosis-related protein expression were quantified by enzyme-linked immunosorbent assay (ELISA) and Western blot, respectively. To investigate the role of S100 calcium-binding protein A9 (S100A9) in AD, both S100A9 knockdown and treatment with the selective S100A9 inhibitor paquinimod were employed. To assess the involvement of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, specific inhibitors targeting PPARα (MK886) and PPARγ (GW9662) were administered.

S100A7A, SERPINB4, KRT16, and S100A9 were identified as potential diagnostic biomarkers for AD, with their expression markedly upregulated in IFN-γ/TNF-α-stimulated HaCaT cells. Knockdown of S100A9 attenuated inflammatory responses and suppressed pyroptosis, as evidenced by reduced levels of cleaved caspase-1, GSDMD-N, and NLRP3. S100A9 deficiency alleviated skin lesions and decreased mast cell infiltration in DNCB-induced AD-like mice. S100A9 inhibitor paquinimod promoted the expression of PPAR-α and PPAR-γ protein levels. MK886 and GW9662 significantly reversed the inhibitory effects of S100A9 knockdown on inflammatory responses and apoptosis.

S100A9 knockdown inhibits pyroptosis and stimulates the PPAR signaling pathway in AD, which offers a potential strategy for AD treatment.