ASCs Activate cGAS-Type I IFNs-IL-7 Axis ViaPseudomonas aeruginosa-Derived Outer Membrane Vesicles to Resolve Pneumonia

AbstractMesenchymal stem cells (MSCs) therapy could efficiently attenuate LPS-induced acute lung injury and Pseudomonas aeruginosa (PA)-induced acute pneumonia. However, the underlying molecular mechanisms are still elusive. Here, we report that PA-derived outer membrane vesicles (OMVs) trigger mouse primary adipose tissue-derived mesenchymal stem cells (ASCs) to upregulate cyclic GMP-AMP synthase (cGAS) for sensing of double-stranded DNA (dsDNA) and the expression of interleukin (IL)-7. Loss of cGAS-interferon (IFN)-β axis abolished the protective function of ASCs to PA-induced acute pneumonia in mice. Mechanistically, OMVs-delivered PA dsDNA primes cGAS-stimulator of interferon genes (STING) signaling pathway and increases the IL-7 production in ASCs via IFN-β signaling. Meanwhile, dsDNA-primed ASCs furthermore amplifies IL-7 expression in primary lung epithelial cells and mouse lung epithelial (MLE)-12 cell line via increased IFN-β. Our findings thus implicate a molecular mechanism that ASCs recognize PA-OMVs-derived dsDNA to secrete IL-7 via activating cGAS, suggesting a potential therapeutic strategy of ASCs transfer for PA-induced lung infection and inflammation.