PPARγ is critical for <i>Mycobacterium tuberculosis</i> induction of Mcl-1 and limitation of human macrophage apoptosis

<div><p>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 <i>Mycobacterium tuberculosis (M</i>.<i>tb)</i>. Although <i>M</i>.<i>tb</i> infection induces PPARγ in human macrophages, which contributes to <i>M</i>.<i>tb</i> 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 <i>M</i>.<i>tb</i> infection. This revealed several genes that are differentially regulated in response to PPARγ silencing during <i>M</i>.<i>tb</i> 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 <i>M</i>.<i>tb</i>, but is limited by virulent <i>M</i>.<i>tb</i>. This suggested that <i>M</i>.<i>tb</i> 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 <i>M</i>.<i>tb</i> 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 <i>M</i>.<i>tb</i> infection, and that pre-clinical therapeutics that inhibit Mcl-1 activity significantly limit <i>M</i>.<i>tb</i> intracellular growth in both human macrophages and an <i>in vitro</i> 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 <i>M</i>.<i>tb</i> infection and new potential targets for host-directed therapy for <i>M</i>.<i>tb</i>.</p>