Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

The pathogenic profile of Pseudomonas aeruginosa is related to its ability to secrete a variety of virulence factors. Quorum sensing (QS) is a mechanism wherein small diffusible molecules, specifically acyl-homoserine lactones, are produced by P. aeruginosa to promote virulence. We show here that macrophage clearance of P. aeruginosa (PAO1) is enhanced by activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). Macrophages treated with a PPAR gamma agonist (pioglitazone) showed enhanced phagocytosis and bacterial killing of PAO1. It is known that PAO1 QS molecules are inactivated by PON-2. QS molecules are also known to inhibit activation of PPAR gamma by competitively binding PPAR gamma receptors. In accord with this observation, we found that infection of macrophages with PAO1 inhibited expression of PPAR gamma and PON-2. Mechanistically, we show that PPAR gamma induces macrophage paraoxonase 2 (PON-2), an enzyme that degrades QS molecules produced by P. aeruginosa. Gene silencing studies confirmed that enhanced clearance of PAO1 in macrophages by PPAR gamma is PON-2 dependent. Further, we show that PPAR gamma agonists also enhance clearance of P. aeruginosa from lungs of mice infected with PAO1. Together, these data demonstrate that P. aeruginosa impairs the ability of host cells to mount an immune response by inhibiting PPAR gamma through secretion of QS molecules. These studies define a novel mechanism by which PPAR gamma contributes to the host immunoprotective effects during bacterial infection and suggest a role for PPAR gamma immunotherapy for P. aeruginosa infections.