Cyclic GMP-AMP synthase (cGAS) is essential for fighting against viruses and bacteria, but how cGAS is involved in host immune response remains largely elusive. Here, we uncover the crucial role of cGAS in host immunity based on a Pseudomonas aeruginosa pulmonary infection model. cGAS-/- mice showed more heavy bacterial burdens and serious lung injury accompanied with exorbitant proinflammatory cytokines than wild-type mice. cGAS deficiency caused an accumulation of mitochondrial DNA in the cytoplasm, which, in turn, induced excessive secretion of proinflammatory factors by activating inflammasome and TLR9 signalling. Mechanistically, cGAS deficiency inhibited the recruitment of LC3 by reducing the binding capacity of TBK-1 to p62, leading to impaired mitophagy and augmented release of mitochondrial DNA. Importantly, cytoplasmic mitochondrial DNA also acted as a feedback signal that induced the activation of cGAS. Altogether, these findings identify protective and homeostasis functions of cGAS against Pseudomonas aeruginosa infection, adding significant insight into the pathogenesis of bacterial infectious diseases.
Keywords: bacterial burdens; cGAS; cytokine secretion; mitochondrial DNA; pulmonary infection.
© 2022 John Wiley & Sons Ltd.