TY - JOUR
T1 - PPARγ is critical for Mycobacterium tuberculosis induction of Mcl-1 and limitation of human macrophage apoptosis
AU - Arnett, Eusondia
AU - Weaver, Ashlee M.
AU - Woodyard, Kiersten C.
AU - Montoya, Maria J.
AU - Li, Michael
AU - Hoang, Ky V.
AU - Hayhurst, Andrew
AU - Azad, Abul K.
AU - Schlesinger, Larry S.
N1 - Funding Information:
This work was supported in part by a National Institutes of Health T32 Fellowship, “Molecular Mechanisms of Lung Inflammation”, award # T32HL007946 (to EA) and a National Institutes of Health T32 Fellowship, "Interdisciplinary Program in Microbe-Host Biology, award #1-T32-AI-112542 (to EA), and National Institutes of Health grants AI059639 and AI052458 (to LSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. William Lafuse and Dr. Murugesan Rajaram [The Ohio State University (OSU)] for guidance with the luciferase reporter assays. The authors would like to acknowledge the facilities and programmatic support of The OSU Biosafety Level 3 Program. We also thank the OSU Campus Microscopy and Imaging Facility, the OSU Comprehensive Cancer Center Genomics Shared Resource for Nucleic Acid services, and Lianbo Yu from the OSU Center for Biostatistics for help analyzing the NanoString data.
Publisher Copyright:
© 2018 Arnett et al. http://creativecommons.org/licenses/by/4.0/
PY - 2018/6
Y1 - 2018/6
N2 - Peroxisome proliferator-activated receptor (PPAR)γ is a global transcriptional regulator associated with anti-inflammatory actions. It is highly expressed in alveolar macrophages (AMs), which are unable to clear the intracellular pathogen Mycobacterium tuberculosis (M.tb). Although M.tb infection induces PPARγ in human macrophages, which contributes to M.tb growth, the mechanisms underlying this are largely unknown. We undertook NanoString gene expression analysis to identify novel PPARγ effectors that condition macrophages to be more susceptible to M.tb infection. This revealed several genes that are differentially regulated in response to PPARγ silencing during M.tb infection, including the Bcl-2 family members Bax (pro-apoptotic) and Mcl-1 (pro-survival). Apoptosis is an important defense mechanism that prevents the growth of intracellular microbes, including M.tb, but is limited by virulent M.tb. This suggested that M.tb differentially regulates Mcl-1 and Bax expression through PPARγ to limit apoptosis. In support of this, gene and protein expression analysis revealed that Mcl-1 expression is driven by PPARγ during M.tb infection in human macrophages. Further, 15-lipoxygenase (15-LOX) is critical for PPARγ activity and Mcl-1 expression. We also determined that PPARγ and 15-LOX regulate macrophage apoptosis during M.tb infection, and that pre-clinical therapeutics that inhibit Mcl-1 activity significantly limit M.tb intracellular growth in both human macrophages and an in vitro TB granuloma model. In conclusion, identification of the novel PPARγ effector Mcl-1 has determined PPARγ and 15-LOX are critical regulators of apoptosis during M.tb infection and new potential targets for host-directed therapy for M.tb.
AB - Peroxisome proliferator-activated receptor (PPAR)γ is a global transcriptional regulator associated with anti-inflammatory actions. It is highly expressed in alveolar macrophages (AMs), which are unable to clear the intracellular pathogen Mycobacterium tuberculosis (M.tb). Although M.tb infection induces PPARγ in human macrophages, which contributes to M.tb growth, the mechanisms underlying this are largely unknown. We undertook NanoString gene expression analysis to identify novel PPARγ effectors that condition macrophages to be more susceptible to M.tb infection. This revealed several genes that are differentially regulated in response to PPARγ silencing during M.tb infection, including the Bcl-2 family members Bax (pro-apoptotic) and Mcl-1 (pro-survival). Apoptosis is an important defense mechanism that prevents the growth of intracellular microbes, including M.tb, but is limited by virulent M.tb. This suggested that M.tb differentially regulates Mcl-1 and Bax expression through PPARγ to limit apoptosis. In support of this, gene and protein expression analysis revealed that Mcl-1 expression is driven by PPARγ during M.tb infection in human macrophages. Further, 15-lipoxygenase (15-LOX) is critical for PPARγ activity and Mcl-1 expression. We also determined that PPARγ and 15-LOX regulate macrophage apoptosis during M.tb infection, and that pre-clinical therapeutics that inhibit Mcl-1 activity significantly limit M.tb intracellular growth in both human macrophages and an in vitro TB granuloma model. In conclusion, identification of the novel PPARγ effector Mcl-1 has determined PPARγ and 15-LOX are critical regulators of apoptosis during M.tb infection and new potential targets for host-directed therapy for M.tb.
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U2 - 10.1371/journal.ppat.1007100
DO - 10.1371/journal.ppat.1007100
M3 - Article
AN - SCOPUS:85049374658
VL - 14
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 6
M1 - e1007100
ER -