High-salt microenvironment worsens the progression of atopic dermatitis via activating the SGK-1-mTOR pathway in...

Atopic dermatitis (AD) is a prevalent chronic skin disease worldwide. Emerging evidence suggests that an elevated salt microenvironment is a unique characteristic of skin lesions in AD patients. Emerging data indicate that lesional skin in AD contains abnormally high salt, yet how this microenvironment affects keratinocytes is unknown. We interrogated the impact of elevated NaCl on barrier function and inflammation using HaCaT cells in vitro, and 2,4-dinitrofluorobenzene (DNFB) and ovalbumin (OVA) treatment induced an AD model of mice in vivo. The interaction between SGK-1, mTOR, STAT3, and NFκB was identified with their roles in AD, analyzed through loss-of-function assays and pharmacological inhibitions. Our results showed that the high-salt microenvironment impaired keratinocyte differentiation and promoted inflammatory cytokine production, thereby exacerbating the disease. Mechanistically, NaCl activated STAT3 via the SGK-1-mTOR signaling pathway in keratinocytes, leading to a decrease in the expression of epidermal barrier proteins. In addition, inflammatory cytokines were increased by NaCl-induced SGK-1-mTOR-NFκB activation. We identified the SGK-1 inhibitor GSK 650394, which could rescue the NaCl-induced blockade of keratinocyte differentiation and inflammatory cytokine production. Moreover, in combination with the JAK inhibitor delgocitinib, GSK 650394 exhibits a synergistic effect in ameliorating AD-like symptoms in vivo. Taken together, our findings demonstrate that the high-salt microenvironment promotes the development of AD by activating the SGK-1-mTOR pathway in keratinocytes, suggesting that an SGK-1 inhibitor could potentially serve as a drug to alleviate AD-like symptoms.