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Abstract
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.
Highlights
Nuclear receptors are a large family of structurally conserved, ligand activated transcription factors, which have a range of functions related to development, homeostasis, metabolism and immunity
We have demonstrated that M.tb, and the M.tb cell wall component mannosylated lipoarabinomannan (ManLAM) enhance PPARγ activity through the mannose receptor (MR) in human macrophages, the host cell niche [4]
Since PPARγ is associated with anti-inflammatory actions [1,2,9], we hypothesized that PPARγ down-regulates a host protective antimicrobial response to facilitate M.tb growth
Summary
Nuclear receptors are a large family of structurally conserved, ligand activated transcription factors, which have a range of functions related to development, homeostasis, metabolism and immunity. Nuclear receptors include receptors for fatty acids such as peroxisome proliferatoractivated receptors (PPARs) [1]. PPARs regulate expression of genes involved in fatty acid metabolism and inflammation (pro- and anti-) and are implicated in diabetes, cancer, and infectious diseases, including tuberculosis (TB) [2,3,4,5,6]. There are three PPAR isoforms, α, β/δ, and γ, which are differentially distributed and activated by different ligands. PPARγ is highly expressed in AMs and is important for AM differentiation [8]. PPARs regulate gene expression through multiple mechanisms, including heterodimerizing with the nuclear receptor retinoid X receptor (RXR), and binding to PPAR response elements (PPREs) in the promoter to regulate gene expression [10]
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