Deletion of PPARγ in lung macrophages provides an immunoprotective response against M. tuberculosis infection in mice

Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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. PPAR gamma 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 PPAR gamma 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 PPAR gamma in vivo during M. tb infection using a macrophage-specific PPAR gamma knock out mouse model with special emphasis on the lung environment. Our data show that the absence of PPAR gamma in lung macrophages reduces the growth of virulent M. tb, enhances pro-inflammatory cytokines and reduces granulomatous infiltration. These findings demonstrate that PPAR gamma activation, which down-regulates macrophage pro-inflammatory responses, impacts the lung's response to M. tb infection, thereby supporting PPAR gamma's role in tuberculosis (TB) pathogenesis.