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

Abstract

fThe 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␥). 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 are also known to inhibit activation of PPAR␥ by competitively binding PPAR␥ receptors. In accord with this observation, 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 impairs the 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 immunoprotective effects during bacterial infection and suggest a role for PPAR␥ immunotherapy for P. aeruginosa infections.

Peroxisome proliferator‐activated receptor‐γ agonists attenuate biofilm formation by Pseudomonas aeruginosa

“…QS molecules have multiple effects on host cells, including disruption of transcriptional signaling mechanisms, to enable establishment of infection. Recently, we have shown that PAO1 and 3O‐C12‐HSL attenuate PPARγ expression in macrophages and lungs of mice that were infected with PAO1 (20). We and others have shown that airway epithelium is critical in mounting host response to P. aeruginosa lung infection (22–26); therefore, we investigated the direct impact of QS gene–expressing PAO1 and 3O‐C12‐HSL on PPARγ levels on airway epithelial cells.…”

“…Recent studies suggest an immunomodulatory role for PPARγ in host response to infection in experimental systems (49, 50). We have recently shown that PPARγ ligands induce PON‐2 and enhance the clearance of P. aeruginosa in macrophages (20). As PPARγ induces PON‐2, which can hydrolyze QS molecules, we hypothesized that PPARγ activation may attenuate biofilm formation.…”

“…P. aeruginosa stock was prepared as previously described (1, 35). Cultures were adjusted to an OD 600 (optical density) of 0.2 (~1.86 × 10 9 colony‐forming units/ml) (20).…”

“…Total cellular RNA was extracted by using the RNeasy RNA extraction kit (Qiagen, Valencia, CA, USA) and Trizol mRNA extraction kit (Thermo Fisher Scientific) according to manufacturer instructions. cDNA was synthesized from 1 μg or 500 ng total RNA by using the SuperScript first‐strand synthesis system (Thermo Fisher Scientific), as previously described (20, 36).…”

Thiazolidinediones and reduced risk of incident bacterial abscess in adults with type 2 diabetes: A population‐based cohort study

“…16 Singh et al speculated that the discrepancy between their results and those reported in the meta-analysis might be explained by different detection biases. In Gram-negative bacterial infections, PPARγ activation increased bacterial killing of pseudomonads, 38,39 and pretreatment with partial-or selective-PPAR-γ agonists ameliorated a pathological change in Escherichia coli meningitis by suppressing interleukin 6 production in the brain. However, the observational studies were prone to unmeasured residual confounding and the "healthy user" effect.…”