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bioRxiv · 10.1101/2022.05.17.492235

OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice

Tanner, L.·Bergwik, J.·Bhongir, R. K.·Pan, L.·Dong, C.·Kalderen, C.·Helleday, T.·Boldogh, I.·Adner, M.·Egesten, A.
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Abstract

Allergic asthma is a complex disease characterized by dyspnea, coughing, chest tightness and airway remodeling, for which there is no cure and is symptomatically treated with inhaled {beta}2-agonist and/or corticosteroids. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, the 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammatory responses. In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-{kappa}B and expression of proinflammatory cytokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed down regulation of Arg1, Mcp1 and Ccl11, and upregulation of the negative regulator of TH2, Bcl6. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Taken together, the data presented in this study suggest a clinically relevant utilization of TH5487 for the treatment of allergic inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/492235v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@2985cdorg.highwire.dtl.DTLVardef@f642corg.highwire.dtl.DTLVardef@79bb1aorg.highwire.dtl.DTLVardef@1eab483_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Tanner, L., Bergwik, J., Bhongir, R. K., Pan, L., Dong, C., Kalderen, C., Helleday, T., Boldogh, I., Adner, M., Egesten, A.. 2022-05-19. OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice. https://doi.org/10.1101/2022.05.17.492235

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