Objective(s): Allergic contact dermatitis (ACD) is a T cell-mediated type IV hypersensitivity reaction to haptens. Its pathogenesis involves keratinocyte dysfunction and dysregulation of the Signal Transducer and Activator of Transcription 3 (STAT3)-signaling pathway. However, the specific role of keratinocyte produced STAT3 in ACD remains unclear. To investigate the effect of keratinocyte (KC)-specific STAT3 conditional knockout on 1-Chloro-2,4-dinitrobenzene (DNCB)-induced ACD in mice.Materials and Methods: We generated keratinocyte-specific STAT3 conditional knockout (cKO) mice (K14-Cre⁺; STAT3flox/flox) and subjected them to DNCB-induced ACD, with STAT3flox/flox littermates as controls. Epidermal barrier function (transepidermal water loss and electrolyte permeability), histopathological inflammation (H&E and toluidine blue staining), and expression of inflammatory mediators (IL-1β, IL-6) were assessed. In vitro, STAT3 was knocked down by siRNA in HaCaT keratinocytes prior to stimulation with TNF-α/IFN-γ, followed by evaluation of inflammatory markers and STAT3 phosphorylation.Results: Keratinocyte-specific STAT3 deletion significantly ameliorated ACD severity, evidenced by reduced TEWL values, enhanced epidermal barrier function, decreased dermatitis scores, reduced clinical dermatitis scores, decreased dermal inflammatory infiltration, lower spleen index, and attenuated mast cell degranulation. Molecular analysis revealed down-regulation of inflammation-related factors (IL-1β, IL-6, TNF-α, JAK2) and significant inhibition of STAT3 phosphorylation. In vitro, STAT3 knockdown significantly suppressed IL-1β, IL-6, JAK2, Caspase-3, and MMP-3 expression in HaCaT cells and reduced STAT3 phosphorylation.Conclusion: Keratinocyte-specific STAT3 deletion alleviates epidermal barrier impairment and skin inflammation in ACD by inhibiting STAT3 phosphorylation and its downstream pro-inflammatory signaling.
Chen et al. (Mon,) studied this question.