Self-DNA mediates tobacco-induced lung inflammation via macrophage-intrinsic cGAS/STING/TBK1 signaling

Abstract Cigarette smoke is a primary risk factor for chronic obstructive pulmonary disease (COPD). While self-DNA sensors coordinated with the immune system are known to contribute to pollutant-induced responses, the exact mechanisms by which dsDNA drives COPD pathogenesis remain unclear. Here, we demonstrated that dsDNA levels are elevated and cGAS/STING/TBK1 signaling is activated in patients with COPD. In-depth investigations using mice models of COPD, including macrophage-specific Lyz2 cre+ Cgas fl/fl , Sting-deficient , and Lyz2 cre+ Tbk1 fl/fl mice, indicated that cigarette smoke extract (CSE) induces mitochondrial reactive oxygen species (mtROS), leading to the overproduction and release of dsDNA and mitochondrial DNA (mtDNA). Furthermore, we found that activation of the downstream IRF3/NF-κB pathway via cGAS/STING/TBK1 signaling promotes the expression of CD80, CD86, and iNOS, thereby driving M1 macrophage polarization. This pathway also mediates the overexpression of type I interferons and related pro-inflammatory cytokines under CSE exposure. Interestingly, released dsDNA further exacerbates these CSE-induced effects by promoting a feedback loop of mtROS overproduction and additional mtDNA release. Notably, blocking cGAS/STING/TBK1 signaling, inhibiting dsDNA release or decreasing mtROS production significantly attenuates M1 pacrophage polarization. Taken together, our findings reveal that the cGAS/STING/TBK1 pathway acts as a critical mediator of dsDNA/mtDNA-driven lung inflammation by regulating M1 macrophage polarization in response to cigarette smoke. Targeting cGAS/STING/TBK1 signaling axis or its associated mtROS/mtDNA networks might offer novel therapeutic strategies against inflammatory lung diseases caused by environmental hazards.