ATG5 suppresses type I IFN-dependent neutrophil effector functions during Mycobacterium tuberculosis infection in mice.

Inflammation is critical for controlling infections but can cause disease when unchecked. During Mycobacterium tuberculosis (Mtb) infection, neutrophil-dominated inflammation is associated with exacerbated disease. ATG5 expression by neutrophils mediates autophagy-independent control of infection but mechanistic understanding of how this regulates protective neutrophil function is lacking. Using genetic mouse models along with in vivo and in vitro infection systems, we report herein that ATG5 is required in neutrophils to suppress type I interferon-induced PAD4-mediated histone citrullination and neutrophil extracellular trap (NET) release. In addition, ATG5 suppresses type I interferon-induced CXCL2 secretion and neutrophil swarming during Mtb infection. Elevated type I IFN signalling and NET release contribute 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 potential target for host-directed therapies.