Title : The role of PPARγ agonists in host defense
Abstract:
Pseudomonas aeruginosa is a major cause of multidrug-resistant infections, particularly in immunocompromised and hospitalized patients. Its pathogenicity is driven by quorum sensing (QS) molecules, such as N-(3-oxo-dodecanoyl)-L-homoserine lactone (3O-C12-HSL), which regulate virulence, promote biofilm formation, and impair host immune responses. Strategies that enhance host defense mechanisms may improve outcomes in resistant infections. Here, we demonstrate that activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) enhances host defense against P. aeruginosa (PAO1). Treatment of macrophages with the PPARγ agonist pioglitazone significantly increased phagocytosis and bacterial clearance. Mechanistically, QS molecules suppressed PPARγ expression and function, in part through competitive receptor binding, and reduced expression of paraoxonase-2 (PON-2), an enzyme that degrades QS molecules. Gene-silencing studies confirmed that PPARγ-mediated bacterial clearance depends on PON-2. In bronchial epithelial cells, PAO1 and 3O-C12-HSL disrupted epithelial barrier integrity by downregulating junctional proteins, including zonula occludens-1, occludin, and claudin-4. Pre-treatment with pioglitazone restored expression of these proteins, improved barrier function, and reduced bacterial permeation. Additionally, PPARγ activation inhibited biofilm formation on epithelial cells via a PON-2–dependent mechanism. In vivo, PPARγ agonist treatment enhanced clearance of P. aeruginosa from the lungs of infected mice. Collectively, these findings identify a novel mechanism by which QS molecules impair host immunity through inhibition of PPARγ signaling. Activation of PPARγ restores immune function, preserves epithelial barrier integrity, and suppresses biofilm formation, highlighting PPARγ as a promising therapeutic target for resistant P. aeruginosa infections.
