Hsp90 inhibitor 17-AAG reduces skin inflammation and inhibits NF-κB/NLRP3 inflammasome activation in DNCB-induced mice and TNF-α/IFN-γ-induced keratinocytes.

Atopic dermatitis (AD) represents the most common inflammatory skin condition with a high burden of disease persistence and relapse. In this study, we aimed to investigate the role of 17-AAG, a Hsp90 inhibitor, in inhibiting skin inflammation in AD and its effect on nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome pathway. Topical application of 17-AAG was found to significantly improve inflammatory skin lesions, reduce epidermal thickness and mast cell infiltration, and decrease levels of proinflammatory cytokines in mice with AD-like skin lesions induced by using 2,4-dinitrochlorobenzene (1 % and 0.5 % DNCB). A reduced extent of p65 phosphorylation with declined protein expressions of NLRP3 and caspase-1 in the dorsal skin lesions of 17-AAG-treated AD mice compared to vehicle-treated AD mice. In HaCaT cells inflamed by tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ), 17-AAG treatment significantly reduced the secretion of proinflammatory cytokines and chemokines, reduce the phosphorylation of p65, and decreased the protein expressions of NLRP3 and caspase-1. These results prove Hsp90 inhibitor 17-AAG could reduce skin inflammation and inhibit NF-κB/NLRP3 inflammasome activation in DNCB-induced mice and TNF-α/IFN-γ-induced human keratinocytes.