GATA2 deficiency promotes a profibrotic program and metabolic dysfunction in alveolar macrophages 2253993

Abstract

Abstract Introduction Alveolar macrophages (AMs) have homeostatic, anti-inflammatory programming to limit tissue damage against minor challenges and catabolize pulmonary surfactant. GATA transcription factors (TFs) shape immune cell fates and GATA2 is expressed in a lung-specific manner in macrophages. Both GATA2 mutations and downregulation in lung macrophages have been associated with chronic pulmonary pathologies in humans, but the role of GATA2 in AM function is not understood. Methods We generated mice with myeloid specific deletion of the GATA2 DNA binding C-terminal zinc finger domain to evaluate its role in AM homeostatic functions and responsiveness to inflammation. To assess homeostatic function, we evaluated AM phagocytic capacity, neutral lipid content, lipid uptake and processing. Given that GATA2 is downregulated in bleomycin-induced fibrosis, we leveraged IL-33 induced type 2 lung inflammation and RNA-seq analysis of sorted AMs to investigate the consequences of GATA2 deficiency on AM gene regulation. Finally, we used sea horse metabolic flux assay to address impact of GATA2 deficiency on the metabolic activity of AMs in steady state and type 2 inflammation. Results We observed that AM homeostatic functions remain unaffected in GATA2 deficiency. In contrast, RNA-seq analysis of AM revealed that GATA2 deficiency increased expression of genes associated with pulmonary fibrosis in IL-33-induced inflammation. Coincident with GATA2-dependent expression of genes in metabolic pathways, seahorse metabolic flux analysis suggests mitochondrial dysfunction in AM. AM GATA2-dependent gene networks are enriched for targets of TFs that regulate AM function, previously demonstrated to interact with GATA2 in other cellular contexts. Conclusion Our findings suggest that GATA2 supports lung-specific macrophage programming by helping to constrain AM metabolic and inflammatory responses, providing mechanistic insight into how GATA2 mutations and decreased expression may contribute to pathology in chronic lung diseases. Funding Source NIH/NHLBI R01HL162658 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)