Lung microbiota-derived SCFAs coordinate alveolar macrophages and γδT cells activation through FFAR2 2154

Description Innate immunity is an important defense against lung bacterial infections, while little is known about the interaction between lung microbiota and innate immunity in lung inflammation. In this study, mice received intratracheal antibiotic treatment and intranasal LPS challenge to induce lung dysbiosis and trigger lung inflammation, respectively. Under LPS stimulation, antibiotic treatment reduced lung inflammation and IL-17A+γδT cells frequency in mice. In addition, the level of IL-1β in the lung and its expression on alveolar macrophages (AMs) were both downregulated by antibiotic treatment. Further, the suppressive effects of antibiotic treatment on lung inflammation and γδT activation were not detected after AMs were depleted by intranasal clodronate administration. Moreover, LC/MS analysis revealed that the levels of microbiota-derived short-chain fatty acids (SCFAs) in the lung decreased significantly by antibiotic treatment. We also found that Ffar2, a major receptor for SCFAs, was highly expressed on AMs through re-analysis of published scRNA-seq data. Additionally, SCFAs promoted IL-1β production, inflammasome activation, and NF-κB phosphorylation in AMs in vitro, which were inhibited by treatment of FFAR2 antagonist. Taken together, our results demonstrated that lung microbiota-derived SCFAs coordinate the activation of AMs and γδT cells through FFAR2, suggesting that lung dysbiosis alters innate immunity-mediated lung inflammation. Funding Sources Supported by Academia Sinica Investigator Award AS-IA-110-L04; National Science and Technology Council 113-2320-B-001-018-MY3 Topic Categories Mucosal and Regional Immunology (MUC)