GATA2 controls alveolar macrophage inflammatory gene expression and metabolic function
Morgan Jackson-Strong, Satarupa Ganguly, Aaron Francis, Flavia Rago, Jitendra Kanshana, Brandon A. Michalides, Lihong Teng, Omkar S. Betsur, Sonia Kruszelnicki, Karsen E. Shoger, Aaron Kim, Kay Bajpai, Amina Suleyman, Abigail Sekyere, Mika Hara, Varsha Sriram, Alok Kumar, Greg M. Delgoffe, Niranjana Natarajan, John F. Alcorn, Alison B. Kohan, Rachel A. Gottschalk
Morgan Jackson-Strong, Satarupa Ganguly, Aaron Francis, Flavia Rago, Jitendra Kanshana, Brandon A. Michalides, Lihong Teng, Omkar S. Betsur, Sonia Kruszelnicki, Karsen E. Shoger, Aaron Kim, Kay Bajpai, Amina Suleyman, Abigail Sekyere, Mika Hara, Varsha Sriram, Alok Kumar, Greg M. Delgoffe, Niranjana Natarajan, John F. Alcorn, Alison B. Kohan, Rachel A. Gottschalk
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Research Article Immunology Pulmonology

GATA2 controls alveolar macrophage inflammatory gene expression and metabolic function

Abstract

Alveolar macrophages (AMs) catabolize lipid-rich pulmonary surfactant to support gas exchange and have antiinflammatory programming to limit tissue damage in response to minor challenges. GATA transcription factors (TFs) shape immune cell fates, and GATA2 is expressed in a lung-specific manner in macrophages. GATA2 mutations and lung macrophage downregulation of GATA2 have been associated with chronic pulmonary pathologies in humans, but the role of GATA2 in coordinating 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 enhanced inflammatory gene expression and metabolic dysfunction in AMs in response to type 2 stimuli. Although homeostatic functions of AMs remain largely intact, GATA2 deficiency increases expression of type 2 response genes during IL-33–induced inflammation. Coincident with GATA2-dependent expression of genes in metabolic pathways, Seahorse metabolic flux analysis indicates that AM metabolism is compromised 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, PPARγ, and other regulators of AM function. Our data suggest that GATA2 modulates AM metabolic and transcriptomic programming to restrain responses and maintain AM identity during inflammation.

Authors

Morgan Jackson-Strong, Satarupa Ganguly, Aaron Francis, Flavia Rago, Jitendra Kanshana, Brandon A. Michalides, Lihong Teng, Omkar S. Betsur, Sonia Kruszelnicki, Karsen E. Shoger, Aaron Kim, Kay Bajpai, Amina Suleyman, Abigail Sekyere, Mika Hara, Varsha Sriram, Alok Kumar, Greg M. Delgoffe, Niranjana Natarajan, John F. Alcorn, Alison B. Kohan, Rachel A. Gottschalk

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Figure 4

IL-33 indirectly induces a robust alveolar macrophage type 2 transcriptomic program.

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IL-33 indirectly induces a robust alveolar macrophage type 2 transcripto...
Mice were treated intranasally with 1 μg of IL-33 or PBS and euthanized 24 hours later for analysis. BAL was isolated from PBS- and IL-33–treated GATA2fl/fl and GATA2LysM-Cre mice; data points represent individual mice pooled from more than 3 independent experiments. (A) Representative BAL flow cytometry plots showing gating strategies for neutrophils, eosinophils, and AMs, and histogram showing AM SiglecF expression in representative PBS- or IL-33–treated mice. (B) SiglecF+CD11c+CD11b– AMs were quantified from BAL; points represent individual mice pooled from 3 independent experiments; significance was determined using 1-way ANOVA with post hoc pairwise testing using Šídák’s multiple-comparison test. (C) Volcano plot of IL-33 differentially expressed genes, showing the –log10 of adjusted P value and log2 expression fold-change in IL-33–treated AMs relative to PBS treatment. (D) AMs were isolated by BAL and treated ex vivo with IL-33 (20 ng/mL), IL-13 (20 ng/mL), or IL-4 (10 ng/mL) for 24 hours. Quantification of mRNA transcripts for type 2 response genes Arg1 and Chil3 (n = 3; mean ± SEM) is representative of 2 independent experiments.