Permissive lung neutrophils facilitate tuberculosis immunopathogenesis in male phagocyte NADPH oxidase-deficient mice

• Published in: PLoS pathogens 2024-08, Vol.20 (8), p.e1012500
• Main Authors: Choi, Eunsol, Choi, Hong-Hee, Kwon, Kee Woong, Kim, Hagyu, Ryu, Ji-Hwan, Hong, Jung Joo, Shin, Sung Jae
• Format: Article
• Language: English
• Subjects: Animals; Biology and Life Sciences; Computer and Information Sciences; Cytokines - metabolism; Development and progression; Disease Models, Animal; Female; Granulomatous Disease, Chronic - immunology; Granulomatous Disease, Chronic - microbiology; Granulomatous Disease, Chronic - pathology; Health aspects; Immune response; Lung - immunology; Lung - microbiology; Lung - pathology; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis - immunology; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - immunology; NADPH Oxidase 2 - metabolism; NADPH Oxidases - genetics; NADPH Oxidases - immunology; NADPH Oxidases - metabolism; Neutrophils; Neutrophils - immunology; Oxidoreductases; Phagocytes; Phagocytes - immunology; Pulmonary tuberculosis; Research and Analysis Methods; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - microbiology; Tuberculosis, Pulmonary - pathology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012500

NADPH oxidase 2 (NOX2) is an enzyme responsible for generating reactive oxygen species, primarily found in phagocytes. Chronic Granulomatous Disease (CGD), along with bacterial infections such as Mycobacterium tuberculosis (Mtb), is a representative NOX2-deficient X-linked disease characterized by uncontrolled inflammation. However, the precise roles of host-derived factors that induce infection-mediated hyperinflammation in NOX2-deficient condition remain incompletely understood. To address this, we compared Mtb-induced pathogenesis in Nox2-/- and wild type (WT) mice in a sex-dependent manner. Among age- and sex-matched mice subjected to Mtb infection, male Nox2-/- mice exhibited a notable increase in bacterial burden and lung inflammation. This was characterized by significantly elevated pro-inflammatory cytokines such as G-CSF, TNF-α, IL-1α, IL-1β, and IL-6, excessive neutrophil infiltration, and reduced pulmonary lymphocyte levels as tuberculosis (TB) progressed. Notably, lungs of male Nox2-/- mice were predominantly populated with CD11bintLy6GintCXCR2loCD62Llo immature neutrophils which featured mycobacterial permissiveness. By diminishing total lung neutrophils or reducing immature neutrophils, TB immunopathogenesis was notably abrogated in male Nox2-/- mice. Ultimately, we identified G-CSF as the pivotal trigger that exacerbates the generation of immature permissive neutrophils, leading to TB immunopathogenesis in male Nox2-/- mice. In contrast, neutralizing IL-1α and IL-1β, which are previously known factors responsible for TB pathogenesis in Nox2-/- mice, aggravated TB immunopathogenesis. Our study revealed that G-CSF-driven immature and permissive pulmonary neutrophils are the primary cause of TB immunopathogenesis and lung hyperinflammation in male Nox2-/- mice. This highlights the importance of quantitative and qualitative control of pulmonary neutrophils to alleviate TB progression in a phagocyte oxidase-deficient condition.