ATG5 suppresses type I IFN-dependent neutrophil swarming and NETosis

SUMMARY Inflammation is critical for controlling infections, but when left unchecked can cause tissue damage and disease. For tuberculosis, the leading cause of death due to infection 1 , host inflammation is responsible for the clinical symptoms 2 , morbidity 2 , and mortality 3,4 . Specifically, neutrophil-dominated inflammation is associated with tuberculosis disease progression 3,5,6 . Therefore, understanding how neutrophil functions are regulated during infection is important for developing ways to prevent disease. Atg5 was the first gene shown to specifically function within neutrophils to promote control of Mycobacterium tuberculosis 7 , the causative agent of tuberculosis. ATG5 is best studied for its role in autophagy 8–11 , however, the protective activity of ATG5 in neutrophils was unexpectedly independent of other autophagy proteins and remained elusive 7 . We report here that ATG5, but not other autophagy proteins, is required in neutrophils to suppress neutrophil NETosis and swarming that occur due to elevated type I interferon levels during M. tuberculosis infection. The elevated level of NETosis that results from loss of ATG5 expression contributes to the early susceptibility of Atg5 fl/fl -LysM-Cre mice during M. tuberculosis infection. NETosis is associated with poor disease outcomes in tuberculosis 12,13 and COVID-19 patients 14,15 , as well as during other inflammatory diseases in humans 16,17 . Our studies identify an essential regulator of NETosis and elucidate previously unappreciated roles for ATG5 during infection, which may inform the design of host-directed therapeutics modulating these pathways.