Pollen-induced oxidative DNA damage response regulates miRNAs controlling allergic inflammation

A mucosal oxidative burst is a hallmark response to pollen exposure that promotes allergic inflammatory responses. Reactive species constituents of oxidative stress signal via the modification of cellular molecules including nucleic acids. One of the most abundant oxidative genomic base damage is 8-oxo-7,8-dihydroguanine (8-oxoG), which is removed from DNA by 8-oxoguanine DNA glycosylase1 (OGG1). OGG1 in complex with 8-oxoG acts as a GDP-GTP exchange factor and induces acute inflammation; however, the mechanism(s) by which OGG1 signaling regulates allergic airway inflammation is not known. Here, we postulate that the OGG1 signaling pathway differentially altered the levels of small regulatory RNAs and increased the expression of T helper 2 (Th2) cytokines in ragweed pollen extract (RWPE)-challenged lungs. To determine this, the lungs of sensitized mice expressing or lacking OGG1 were challenged with RWPE and/or with OGG1's excision product 8-oxoG. The responses in lungs were assessed by next-generation sequencing, as well as various molecular and histological approaches. The results showed that RWPE challenge induced oxidative burst, damage to DNA and activated OGG1 signaling, resulting in the differential expression of 84 microRNAs, which then exacerbated antigen-driven allergic inflammation and histological changes in the lungs. The exogenous administration of the down-regulated let-7b-p3 mimetic or inhibitors of up-regulated miR23a or miR27a decreased eosinophil recruitment, mucus and collagen production via controlling the expression of IL4, IL5, and IL13. Together, these data demonstrate the roles of OGG1 signaling in the regulation of antigen-driven allergic immune responses via differential expressions of microRNAs upstream of Th2 cytokines and eosinophils.

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