α-Boswellic acid alleviates atopic dermatitis via MME-mediated restoration of IL-18 BP/IL-18 axis homeostasis.

ObjectiveAtopic dermatitis (AD) involves complex immune dysregulation, with the IL-18 BP/IL-18 axis emerging as a critical yet underexplored regulator of pathological inflammation. While α-boswellic acid (α-BA) has shown therapeutic promise in AD, its role in regulating the IL-18 BP/IL-18 axis under the inflammatory microenvironment is unclear. This study aimed to elucidate whether α-BA could restore IL-18 BP/IL-18 homeostasis and thus suppress inflammation while preserving immune defense.MethodsA two-sample Mendelian randomization (MR) analysis using summary-level genome-wide association data was conducted to evaluate the potential causal contribution of circulating IL-18 levels to AD susceptibility. DNFB-induced AD mouse model and TNF-α/IFN-γ-stimulated HaCaT cells were used to evaluate α-BA's effects on barrier function, cytokine profiles, and IL-18 BP/IL-18 axis modulation. RNA sequencing (RNA-seq) was employed to identify the critical mediator of α-BA.ResultsMR analysis showed a statistically significant but modest association between genetically predicted circulating IL-18 levels and AD risk (OR=1.003, P<0.05). α-BA restored epidermal barrier integrity in AD mice and normalized serum IgE and IL-13 levels. In HaCaT cells, α-BA treatment rebalanced the IL-18 BP/IL-18 axis and reduced pro-inflammatory cytokines. In addition, α-BA inhibited MyD88/NF-κB signaling, whereas blocking the IL-18 BP/IL-18 axis abolished this effect. RNA-seq identified metalloendopeptidase (MME) as a candidate molecule associated with α-BA treatment, and pharmacological inhibition of MME attenuated the effects of α-BA on the IL-18 BP/IL-18 axis.Conclusionsα-BA may alleviate AD by modulating the IL-18 BP/IL-18 axis and downstream MyD88/NF-κB signaling pathways. MME may contribute to α-BA-mediated regulation of the IL-18 BP/IL-18 axis.