ATG5 suppresses type I interferon-dependent neutrophil swarming and NET release

Inflammation is critical for controlling infections but can cause disease when unchecked. For tuberculosis, the leading cause of death by infection, neutrophil-dominated inflammation is associated with disease progression, emphasizing the need to understand how neutrophil functions are regulated during Mycobacterium tuberculosis infection. Atg5 was the first gene shown to specifically function within neutrophils to promote control of M. tuberculosis. ATG5 is best studied for its role in autophagy, however, the protective activity of ATG5 in neutrophils was unexpectedly independent of other autophagy proteins and remained elusive. We report that ATG5 is required in neutrophils to suppress type I interferon-induced neutrophil extracellular trap (NET) release and swarming during M. tuberculosis infection. Elevated NET release contributes to the early susceptibility of Atg5fl/fl-LysM-Cre mice during infection. These findings identify ATG5 as a master regulator of how type I interferon influences neutrophil responses during infection, revealing a new potential target for host-directed therapies. Overall design: Mice were infected with 100 CFUs of aerosolized M. tuberculosis per lung using an Inhalation Exposure System (Glas-Col). Neutrophils were isolated from the lung at 14dpi by Ly6G enrichment according to themanufacturer's instructions (Miltenyi, 130-120-337).