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 (PPARγ). Macrophages treated with a PPARγ 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 PPARγ by competitively binding PPARγ receptors. In accord with this observation, we found that infection of macrophages with PAO1 inhibited expression of PPARγ and PON-2. Mechanistically, we show that PPARγ 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 PPARγ is PON-2 dependent. Further, we show that PPARγ 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 PPARγ through secretion of QS molecules. These studies define a novel mechanism by which PPARγ contributes to the host immunoprotective effects during bacterial infection and suggest a role for PPARγ immunotherapy for P. aeruginosa infections.
Department of Veterans Affairs, Atlanta VAMC, Decatur, Georgia, USA.|Division of Pulmonary, Allergy, and Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia, USA.
Brahmchetna
B
Bedi
Department of Veterans Affairs, Atlanta VAMC, Decatur, Georgia, USA.|Division of Pulmonary, Allergy, and Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia, USA.
Zhihong
Z
Yuan
Department of Immunology, Pusan University, Yangsan, South Korea.
Myungsoo
M
Joo
Department of Veterans Affairs, Atlanta VAMC, Decatur, Georgia, USA.|Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Susu M
SM
Zughaier
Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
Joanna B
JB
Goldberg
Department of Veterans Affairs, Atlanta VAMC, Decatur, Georgia, USA.|Division of Dermatology, Emory University, Atlanta, Georgia, USA.
Jack L
JL
Arbiser
Department of Veterans Affairs, Atlanta VAMC, Decatur, Georgia, USA.|Division of Pulmonary, Allergy, and Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia, USA.
C Michael
CM
Hart
Department of Veterans Affairs, Atlanta VAMC, Decatur, Georgia, USA ruxana.sadikot@emory.edu.|Division of Pulmonary, Allergy, and Critical Care, and Sleep Medicine, Emory University, Atlanta, Georgia, USA.
Ruxana T
RT
Sadikot
D000818:Animals; D043303:Aryldialkylphosphatase / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D050296:Microbial Viability / Q000276:immunology; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology*
D008024:Ligands; D047495:PPAR gamma; C578990:PON2 protein, mouse; D043303:Aryldialkylphosphatase