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Legionella pneumophila Outer Membrane Vesicles: Isolation and Analysis of Their Pro-inflammatory Potential on Macrophages
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ASCs Activate cGAS-Type I IFNs-IL-7 Axis Via Pseudomonas aeruginosa-Derived Outer Membrane Vesicles to Resolve

Caixia Di1,2, Yanshan Jiang1,2, Lulu Li3

  • 1Department of Pulmonary and Critical Care Medicine, Shanghai Key Discipline for Respiratory Diseases, Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Stem Cells (Dayton, Ohio)
|February 24, 2023
PubMed

Insights

Adipose-derived mesenchymal stem cells (ASCs) recognize Pseudomonas aeruginosa (PA) outer membrane vesicles (OMVs) by sensing double-stranded DNA (dsDNA). This interaction activates the cyclic GMP-AMP synthase (cGAS) pathway, leading to interleukin-7 (IL-7) secretion and protection against PA-induced pneumonia.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Mesenchymal stem cells (MSCs) show therapeutic potential for acute lung injury and pneumonia.
  • The precise molecular mechanisms by which MSCs exert protective effects against Pseudomonas aeruginosa (PA) infections remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the protective effects of adipose-derived mesenchymal stem cells (ASCs) against PA-induced acute pneumonia.
  • To investigate the role of cyclic GMP-AMP synthase (cGAS) and its downstream signaling in ASC-mediated immune responses to PA.

Main Methods:

  • Primary mouse adipose tissue-derived ASCs were treated with PA-derived outer membrane vesicles (OMVs).
  • Expression levels of cGAS, interferon-beta (IFN-β), and interleukin-7 (IL-7) were analyzed.
  • The function of the cGAS-IFN-β axis was assessed in vivo using a mouse model of PA-induced pneumonia.
  • dsDNA sensing and STING pathway activation by OMVs were investigated.

Main Results:

  • PA-OMVs induced ASCs to upregulate cGAS and subsequently express IL-7.
  • The cGAS-IFN-β signaling pathway was crucial for ASCs to protect against PA-induced pneumonia in mice.
  • OMVs-delivered dsDNA activated the cGAS-STING pathway in ASCs, leading to IFN-β-mediated IL-7 production.
  • Activated ASCs amplified IL-7 expression in lung epithelial cells via IFN-β.

Conclusions:

  • ASCs recognize dsDNA from PA-OMVs through the cGAS pathway, leading to IL-7 secretion and conferring protection against PA lung infections.
  • This study reveals a novel mechanism of ASC-mediated innate immunity against bacterial pneumonia.
  • Targeting the ASC-cGAS-IL-7 axis presents a potential therapeutic strategy for PA-induced lung inflammation and infection.
Keywords:
Pseudomonas aeruginosacGASmesenchymal stem cellsouter membrane vesiclespneumonia

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