Myeloid ATG7 Functions as a Sentinel for Pulmonary Defense Against Infection with Nontuberculous Mycobacteria

Nontuberculous mycobacterial pulmonary diseases (NTM-PD) are becoming increasingly prevalent and incident, and heightened antibiotic resistance presents a considerable challenge to clinicians. Despite this, our understanding of the factor(s) contributing to host defense against NTM-PD remains incomplete. Herein, we report that the myeloid autophagy-related gene (ATG) 7 promotes host protective responses against NTM-PD by mitigating excessive pathological inflammation, oxidative stress, and cell death associated with neutrophil infiltration. Patients with NTM-PD displayed a notable reduction in ATG7 expression in peripheral blood mononuclear cells and in necrotic lesions at disease sites. Mice with deletion of Atg7 specifically in myeloid cells (Atg7 cKO) exhibited a significant increase in lung bacterial load during infection. Spatial and bulk RNA-seq analyses, as well as biological experiments, revealed heightened myeloid cell infiltration, excessive inflammation, and mitochondrial damage in Atg7 cKO lung tissues. Furthermore, myeloid Atg7-deficient mice showed upregulated apoptosis, necrosis, and GSDME-associated cell death, along with the formation of neutrophil extracellular traps, in the lung tissues during NTM-PD. However, Atg7-deficient macrophages showed only marginal differences in inflammation and cell death in vitro during NTM infection. Our findings demonstrate that myeloid ATG7 plays a major role in non-cell-autonomous protection against NTM-PD by alleviating neutrophil-associated pathological inflammation and cell death. Overall design: To investigate the function ATG7 in the NTM-infected mice, we established C57/BL6 mouse in which each ATG7 gene has been conditional knocked out.