Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear transcription factor belonging to the superfamily of ligand-activated nuclear receptors. It is activated by diverse endogenous lipid metabolites as well as by exogenous ligands such as the thiazolidinediones. It regulates cellular metabolism, proliferation, differentiation, and inflammation, the latter in part through trans-repression of pro-inflammatory cytokines. PPARγ is highly expressed in alternatively activated alveolar macrophages (AMs), a primary host cell for airborne Mycobacterium tuberculosis (M.tb). Our previous in vitro study identified the importance of PPARγ activation through the mannose receptor (CD206) on human macrophages in enabling M. tb growth. The aim of the current study was to investigate the role of PPARγ in vivo during M. tb infection using a macrophage-specific PPARγ knock out mouse model with special emphasis on the lung environment. Our data show that the absence of PPARγ in lung macrophages reduces the growth of virulent M. tb, enhances pro-inflammatory cytokines and reduces granulomatous infiltration. These findings demonstrate that PPARγ activation, which down-regulates macrophage pro-inflammatory responses, impacts the lung's response to M. tb infection, thereby supporting PPARγ′s role in tuberculosis (TB) pathogenesis.
Highlights
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear transcription factor belonging to the superfamily of ligand-activated nuclear receptors
Survival of M.tb is increased in alternatively activated macrophages [21,22,23,24] and we have previously reported that PPARγ plays a role in promoting M.tb growth in human macrophages [8], at least in part through transcriptional regulation of apoptosis
We investigated whether PPARγ KO macrophages are able to better control M.tb intracellular survival in vitro and whether the lung environment uniquely impacts the effects of PPARγ during M.tb infection
Summary
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear transcription factor belonging to the superfamily of ligand-activated nuclear receptors. PPARγ activation generates a host cell that is more susceptible to M.tb and we hypothesize that PPARγ in lung macrophages plays an important role in modulating immune responses during M.tb infection The aim of this current study was to investigate the role of PPARγ in vivo during M.tb infection using the mouse aerosol M.tb infection model. Our data demonstrate that absence of PPARγ in macrophages decreases bacterial burden, increases pro-inflammatory cytokines and reduces total lung inflammation. These findings along with previously published work demonstrate the importance of PPARγ activation in promoting M.tb infection during the innate immune response
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