GATA2 deficiency drives a profibrotic program and metabolic dysfunction in alveolar macrophages
Alveolar macrophages (AMs) have homeostatic, anti-inflammatory programming to limit tissue damage in response to minor challenge and the distinct, lung-specific function of catabolizing lipid-rich pulmonary surfactant to support gas exchange. GATA transcription factors (TFs) have been well established to cooperate with and antagonize other TFs to shape immune cell fates and GATA2 is expressed in a lung-specific manner in macrophages. Both mutations and lung macrophage downregulation of GATA2 have been associated with chronic pulmonary pathologies in humans, but the role of GATA2 in shaping AM function is not well defined. Using mice with myeloid-specific deletion of the GATA2 DNA binding C-terminal zinc finger domain, we show that GATA2 deficiency promotes a profibrotic state and metabolic dysfunction in AMs in response to type 2 stimuli. While homeostatic functions of AMs remained largely intact, GATA2 deficiency increased expression of genes associated with pulmonary fibrosis in response to IL-33-induced inflammation. Coincident with GATA2-dependent expression of genes in metabolic pathways, seahorse metabolic flux analysis suggests that AM metabolism is compromised, likely due to mitochondrial dysregulation, in the absence of GATA2. AM GATA2-dependent gene networks are enriched for targets of TFs previously demonstrated to interact with GATA2 in other cellular contexts, including PU.1, PPAR?, and other TFs that regulate AM homeostatic and inflammatory function. Thus, GATA2 mediates AM metabolic and transcriptomic programming to limit responses that support the development pulmonary fibrosis. Overall design: To investigate the role of GATA2 in alveolar macrophages, we generated a myeloid-specific Gata2 deficient mice, designed so that the DNA binding C-terminal zinc finger domain (exon 5) is deleted in the presence of myeloid-specific Cre recombinase. RNA-seq profiling was performed on sorted murine alvolar macrophages 24 hours after intranasal exposure to PBS or IL-33.