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

Background: 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.

Methods: 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.

Results: 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.

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

Atopic dermatitis; PPAR signaling pathway; Pyroptosis; S100A9.