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 increased proinflammatory cytokine production from macrophages during M. tuberculosis infection, loss of ATG5 in innate immune cells also results in an early induction of TH17 responses. Despite prior published in vitro cell culture experiments supporting a role for autophagy in controlling M. tuberculosis replication in macrophages, the effects of autophagy on inflammatory responses occur without changes in M. tuberculosis burden in macrophages. 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.
Host autophagy had been associated with the control of Mycobacterium tuberculosis (Mtb) infection due to its ability to sequesters microorganisms through a process termed "xenophagy" (1-4). Xenophagy purportedly limits Mtb replication within infected macrophages (1-4). However, studies in mice using a standard low-dose infection model demonstrated that xenophagy in infected phagocytes is not required to control Mtb pathogenesis (5,6). Instead, an autophagy-independent function of ATG5 in myeloid cells controls low-dose Mtb infection through limiting neutrophilic inflammation5. Hitherto, an in vivo role for autophagy during Mtb infection remained to be elucidated. We report herein that autophagy in myeloid cells mediates protection against high-dose Mtb infection, providing the first evidence for a role for autophagy in myeloid cells during Mtb infection in vivo. With the exception of ATG5, the autophagy proteins required to control high-dose Mtb infection are dispensable for host defense against a standard low-dose Mtb infection. Specifically, autophagy is required in CD11c+ cells, but is dispensable in neutrophils, to control a high-dose Mtb infection in the lung. The role for autophagy is not to directly degrade Mtb in macrophages through xenophagy, but mainly to limit myeloid-derived suppressor cell accumulation and to promote sustained protective T cell responses. Together, our data highlight a novel role for autophagy in controlling Mtb infection, distinct from that of Atg5 during low-dose Mtb infection, or any previously reported roles for autophagy. In addition, our finding that the result of a pathogen-plus-susceptibility gene interaction is dependent on pathogen burden has important implications on our understanding of how Mtb infection in humans can lead to a spectrum of outcomes, the variables that contribute to autophagy gene function during infection and inflammation, and the potential use of autophagy modulators in clinical medicine.
Asthma affects nearly 260 million people worldwide, where severe asthma cases represent the most difficult to treat due to corticosteroid insensitivity. Severe asthma is associated with higher levels of TH17 and TH1 responses, accompanied by neutrophil dominated inflammation. Better understanding of the immune responses to airway allergens that promote or protect against severe asthma is critical for identifying ways to treat these patients. Single nucleotide polymorphisms in the ATG5 gene, which encodes for a protein required for the cellular recycling process of autophagy, has been associated with higher risk for developing severe asthma. However, the exact role for ATG5 during allergic inflammation and whether other autophagy proteins are involved remains elusive. Using genetic tools to dissect the roles for ATG5 in innate immune cells in house dust mite (HDM)-challenged mice, we have identified a specific role for ATG5 in CD11c+ lung macrophages and dendritic cells for suppressing TH17 responses and neutrophil accumulation. We found that this role for ATG5 in CD11c+ cells to regulate neutrophil accumulation during allergic airway inflammation also required other autophagy proteins but did not involve regulation of inflammasome, despite higher levels of IL-1b and Caspase 1 in the lungs of mice lacking autophagy in innate immune cells. Our data support a role for autophagy in CD11c+ lung macrophages and dendritic cells to promote an immune response to airway allergens that is associated with less severe asthma by suppressing TH17 responses and neutrophil accumulation in the lung.
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 protein in lung resident macrophages and dendritic cells that are required to suppress inflammatory responses that are associated with poor control of M. tuberculosis infection.
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