AUTHOR=Nosaka Nobuyuki , Martinon Daisy , Moreira Debbie , Crother Timothy R. , Arditi Moshe , Shimada Kenichi 

TITLE=Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00207

DOI=10.3389/fimmu.2020.00207

ISSN=1664-3224

ABSTRACT=Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome. Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and high-volume mechanical ventilation (MV). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 suffered severe hypoxemia and increased lung permeability with significantly higher IL-1β release into alveolar space. Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation and lung permeability, followed by significantly suppressed IL-1β production. Intratracheal treatment with anti-IL-1β monoclonal antibody (mAb) significantly improved arterial oxygenation as well as lung permeability. On the other hand, deletion of IL-1α gene or use of anti-IL-1α mAb provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.