Deletion of PPARγ in Alveolar Macrophages Is Associated with a Th-1 Pulmonary Inflammatory Response

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is constitutively expressed at high levels in healthy alveolar macrophages, in contrast to other tissue macrophages and blood monocytes. PPARgamma ligands have been shown to down-regulate IFN-gamma-stimulated inducible NO synthase (iNOS) in macrophages. Because NO is an important inflammatory mediator in the lung, we hypothesized that deletion of alveolar macrophage PPARgamma in vivo would result in up-regulation of iNOS and other inflammatory mediators. The loss of PPARgamma in macrophages was achieved by crossing floxed (+/+) PPARgamma mice and a transgenic mouse containing the CRE recombinase gene under the control of the murine M lysozyme promoter (PPARgammaKO). Alveolar macrophages were harvested by bronchoalveolar lavage (BAL). Lymphocytes (CD8:CD4 ratio = 2.8) were increased in BAL of PPARgammaKO vs wild-type C57BL6; p < or = 0.0001. Both iNOS and IFN-gamma expression were significantly elevated (p < or = 0.05) in BAL cells. Th-1 associated cytokines including IL-12 (p40), MIP-1alpha (CCL3), and IFN inducible protein-10 (IP-10, CXCL10) were also elevated. IL-4 and IL-17A were not detected. To test whether these alterations were due to the lack of PPARgamma, PPARgamma KO mice were intratracheally inoculated with a PPARgamma lentivirus construct. PPARgamma transduction resulted in significantly decreased iNOS and IFN-gamma mRNA expression, as well as reduced BAL lymphocytes. These results suggest that lack of PPARgamma in alveolar macrophages disrupts lung homeostasis and results in a Th1-like inflammatory response.