The pathogenic profile of P. 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 homo serine lactones, are produced by P. aeruginosa to promote virulence. Here we show that macrophage clearance of P. aeruginosa (PAO1) is enhanced by activation of the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPAR¿). Macrophages treated with a PPAR¿ agonist (pioglitazone) showed enhanced phagocytosis and bacterial killing of PAO1. It is known that PAO1 QS molecules are inactivated by PON-2. QS Molecules also known to inhibit activation of PPAR¿ by competitively binding PPAR¿ receptors. In accord, we found that, infection of macrophages with PAO1 inhibited expression of PPAR¿ and PON-2. Mechanistically, we show that PPAR¿ 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¿ is PON-2 dependent. Further we show that PPAR¿ agonists also enhance clearance of P.aeruginosa from lungs of mice infected with PAO1. Together these data demonstrate that P. aeruginosa impair ability of host cells to mount an immune response by inhibiting PPAR¿ through secretion of QS molecules. These studies define a novel mechanism by which PPAR¿ contributes to the host immune-protective effects during bacterial infection and suggest a role for PPAR¿ immunotherapy for P. aeruginosa infections.

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