Mechanisms Of The CGAS/STING Pathway In Lung Flora-mediated PM2.5 Effects

Pulmonary microbial communities are prevalent in the pulmonary tissues of many organisms and play a critical role in the development of pulmonary disease.In 2013,the World Health Organization identified PM2.5 as "Class Ⅰ carcinogen".Studies have shown that exposure to PM2.5 can change the microbial composition of the lung and its metabolites.The mechanisms by which exposure to PM2.5 interacts with the lung flora are still not clear.cGAS is an intracellular DNA receptor that is closely related to microorganisms.In this study,we focused on lung microbes to study the role of lung microbes and the cGAS signaling pathway in PM2.5 exposure:by constructing cGAS-/-mice from the lung and mice cleared by the lung microbiota,the purpose of this study was to determine the effect of the cGAS signaling pathway on the effect of PM2.5 exposure and the role and mechanism of lung microbes in this process.1.PM2.5 conditioned cGAS-/-mice.In this study,we constructed a mouse model of subacute exposure by tracheal drop injection of PM2.5 and analyzed lung injury,inflammation,and genomic instability in cGAS+/+ and cGAS-/-mice.We found that PM2.5 can affect toxic effects caused by exposure to PM2.5 via the cGAS signalling pathway.In comparison to cGAS+/+ mice,cGAS-/-mice exhibited significantly lower levels of lung injury,fibrosis,inflammation and expression of yH2AX following exposure to PM2.5.2.PM2.5 effects on cGAS-/-mice conditioned via lung microbes.To analyze the effects of cGAS signaling pathway and the lung microbiota on conditions of lung injury,inflammation,and genomic instability in mice,we constructed a mouse model of subacute exposure using a PM2.5 tracheal drip injection.We found that:1)the presence of healthy lung microbes could effectively reduce toxicities caused by exposure to PM2.5.We found that the degree of lung injury,pulmonary fibrosis,inflammation,and genomic instability caused by PM2.5 exposure was significantly higher following the ablation of lung microbes.2)PM2.5 acted directly on cGAS to influence its toxic effects due to exposure.In cGAS+/+ mice,the degree of lung injury,fibrosis,inflammation,and genomic instability was significantly greater than in cGAS-/-mice.3)PM2.5 was partially dependent on lung microbes acting on the cGAS-STING signaling pathway to influence the toxic effects resulting from PM2.5 exposure.The expression of the cGAS gene and the presence of the lung microbiota may have an effect on the expression of STlNG and IFN-al,the downstream signals of the cGAS.Normal cGAS gene expression and the presence of the lung microbiota may also co-promote IFN-al expression.In conclusion,this study investigated that cGAS and lung microbiome have important roles in lung injury,fibrosis,inflammatory response,and genomic instability in mice exposed to PM2.5.This study will reveal the toxicological effects and mechanism of action of PM2.5 from a novel perspective,which provides a new perspective for an in-depth understanding of PM2.5 toxic effects and mechanisms,and provides new possible targets for intervention in lung diseases.