8-oxo-7,8-dihydroguanosine (8-oxo-Guo) drives pulmonary inflammatory pathways through pattern recognition receptors

8-oxo-7,8-dihydroguanosine (8-oxo-Guo) is a key biomarker of oxidative stress and nucleic acid damage, the levels of which positively correlate with aging and age-related diseases. Notably, in inflammatory diseases, 8-oxo-Guo levels are significantly elevated. In vivo mouse experiments showed that a tail vein injection of 8-oxo-Guo increased inflammatory factor expression in peripheral blood and lung tissue and increased the proportion of M1-type macrophages in bronchoalveolar lavage fluid, indicating the induction of macrophage polarization and pulmonary inflammation. In vitro studies of mouse alveolar macrophages revealed that 8-oxo-Guo activates inflammatory pathways via Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), Toll-like receptor 2 (TLR2), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) receptors synergistically with single-stranded RNA (e.g., polyuridylic acid or uracil-rich microRNA). NOD2 appears as a core regulatory target, in which its inhibition effectively reduces inflammation. The present study elucidates a novel mechanism whereby endogenous 8-oxo-Guo drives pulmonary inflammation through these receptors in alveolar macrophages, indicating that 8-oxo-Guo is a key inflammatory initiator in alveolar macrophages and mice. 8-oxo-Guo and ssRNA synergistically activate the NOD2-mediated PRR signaling pathway to enhance inflammation. (Created with Figdraw, ID: AARTY1163b) • 8-oxo-Guo actively drives pulmonary inflammation, beyond being a mere biomarker. • 8-oxo-Guo induces M1 macrophage polarization and elevates inflammatory factors. • 8-oxo-Guo synergizes with ssRNA to activate inflammation via the PRRs. • NOD2 is the core regulator in this synergistic activation by 8-oxo-Guo and ssRNA. • A novel mechanism that oxidative RNA directly regulates pulmonary inflammation.