%0 Journal Article
%T PPAR¦Ã is critical for Mycobacterium tuberculosis induction of Mcl-1 and limitation of human macrophage apoptosis
%A Abul K. Azad
%A Andrew Hayhurst
%A Ashlee M. Weaver
%A Eusondia Arnett
%A Kiersten C. Woodyard
%A Ky V. Hoang
%A Larry S. Schlesinger
%A Maria J. Montoya
%A Michael Li
%J PLOS Pathogens: A Peer-Reviewed Open-Access Journal
%D 2018
%R https://doi.org/10.1371/journal.ppat.1007100
%X Peroxisome proliferator-activated receptor (PPAR)¦Ã 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 PPAR¦Ã 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 PPAR¦Ã effectors that condition macrophages to be more susceptible to M.tb infection. This revealed several genes that are differentially regulated in response to PPAR¦Ã 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 PPAR¦Ã to limit apoptosis. In support of this, gene and protein expression analysis revealed that Mcl-1 expression is driven by PPAR¦Ã during M.tb infection in human macrophages. Further, 15-lipoxygenase (15-LOX) is critical for PPAR¦Ã activity and Mcl-1 expression. We also determined that PPAR¦Ã 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 PPAR¦Ã effector Mcl-1 has determined PPAR¦Ã and 15-LOX are critical regulators of apoptosis during M.tb infection and new potential targets for host-directed therapy for M.tb.
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007100