ABSTRACT
The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival during M. tuberculosis infection, however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment during M. tuberculosis infection, we used different mouse strains that conditionally delete Atg5 in specific cell types. We found that ATG5 is required in CD11c+ cells (lung macrophages and dendritic cells) to control the production of proinflammatory cytokines and chemokines during M. tuberculosis infection, which would otherwise promote neutrophil recruitment. This role for ATG5 is autophagy-dependent, but independent of mitophagy, LC3-associated phagocytosis, and inflammasome activation, which are the most well-characterized ways that autophagy proteins regulate inflammation. In addition to the increase in proinflammatory cytokine production during M. tuberculosis infection, loss of ATG5 in innate immune cells also results in an early induction of TH17 responses. These findings reveal new roles for autophagy proteins in lung resident macrophages and dendritic cells that are required to suppress inflammatory responses that are associated with poor control of M. tuberculosis infection.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
¶ This work was supported by NIH grants R01 AI132697 and U19 AI142784, a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award, and the Philip and Sima Needleman Center for Autophagy Therapeutics and Research to C.L.S., a Potts Memorial Foundation postdoctoral fellowship to R.L.K., and a National Science Foundation Graduate Research Fellowship DGE-1143954 and the NIGMS Cell and Molecular Biology Training Grant GM007067 to J.M.K.