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

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is constitutively expressed at high levels in healthy alveolar macrophages, in contrast to other tissue macrophages and blood monocytes. PPAR gamma 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 PPAR gamma in vivo would result in up-regulation of iNOS and other inflammatory mediators. The loss of PPAR gamma in macrophages was achieved by crossing floxed (+/+) PPAR-gamma mice and a transgenic mouse containing the CRE recombinase gene under the control of the murine M lysozyme promoter (PPAR gamma KO). Alveolar macrophages were harvested by bronchoalveolar lavage (BAL). Lymphocytes (CD8:CD4 ratio = 2.8) were increased in BAL of PPAR gamma KO vs wild-type C57BL6; p <= 0.0001. Both iNOS and IFN-gamma expression were significantly elevated (p <= 0.05) in BAL cells. Th-1 associated cytokines including IL-12 (p40), MIP-1 alpha (CCL3), and IFN inducible protein-10 (IP-10, CXCL10) were also elevated. IL-41 and IL-17A were not detected. To test whether these alterations were due to the lack of PPAR gamma, PPAR gamma KO mice were intratracheally inoculated with a PPAR gamma lentivirus construct. PPAR-gamma transduction resulted in significantly decreased iNOS and IFN-gamma mRNA expression, as well as reduced BAL lymphocytes. These results suggest that lack of PPAR gamma in alveolar macrophages disrupts lung homeostasis and results in a Th1-like inflammatory response. The Journal of Immunology, 2009, 182: 5816-5822.