Probiotic DNA epigenetically modulates KDM4A degradation to mitigate airway allergy

Dysfunction of Type 1 regulatory T cells (Tr1 cells) is a key in airway allergy (AA), but mechanisms are unclear. This study explored if probiotic DNA restores Tr1 function in AA mice via USP14 and KDM4A. An AA mouse model (dust mite extracts) was used; techniques included flow cytometry (Tr1 function/Th2 polarization), ChIP, and ubiquitin immunoblotting (KDM4A, Il-10 promoter epigenetics). KDM4A-deficient CD4⁺ T cell mice showed spontaneous airway Th2 polarization (AA-like pathology). AA mice had impaired Tr1 immunosuppression, lower KDM4A at Il-10 promoter (correlating with reduced IL-10/Tr1 suppression), increased Il-10 promoter H3K9me3/hypermethylation, and reduced USP14. Probiotic DNA elevated USP14, restored KDM4A, enhanced Tr1 function, and reduced AA responses. In conclusion, reduced Il-10-promoter KDM4A drives Tr1 dysfunction in AA; probiotic DNA mitigates AA via USP14 upregulation (restoring KDM4A/Tr1 function), a potential therapeutic target.