Abstract 560: Role of Paraoxonase 2 In Innate Immune Response in an Acute Infection Model
Background (3-oxododecanoyl)-L-homoserine lactone (3OC12-HSL) is a quorum-sensing molecule produced by certain classes of gram-negative microbial pathogens, such as Pseudomonas aeruginosa (PAO1), is involved in the regulation of virulence factors and alters the function of the host cells. Previously, We have shown that paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL in murine tracheal epithelial cells. In this study, we examined the physiological role of PON2 in innate host defense using the PA01-induced acute infection mouse model.
Materials and Results We demonstrates that both intact cells and membrane-enriched protein lysates obtained from PON2-deficient (PON2-def) macrophages reveal a marked impairment in their ability to hydrolyze 3OC12-HSL. PON2 is neither up-regulated nor down-regulated in response to 3OC12-HSL in control macrophages. In an ex vivo model, macrophages derived from PON2-def mice show an increase in ER stress-mediated oxidative stress and defective PI3 kinase/AKT activation, leading to reduced phagocytes function compared to control macrophages following 3OC12-HSL treatment. Moreover, p85, a regulatory subunit of PI3-kinase, shows higher tyrosine nitration in the macrophage of PON2-def mice which is associated with phagocytic function. Restoration of PON2 in the macrophages reduces the ER stress mediated oxidative stress and improves the phagocytosis function in response to 3OC12-HSL treatment. Furthermore, following administration of 1.6x107CFU of PAO1, a decrease in bacterial clearance is found in the lungs, and liver of PON2-def mice by 5.7, and 14.8 fold, respectively.
Conclusion Increased ER stress mediated oxidative stress decreases phagocytosis function in the macrophages of PON2-def mice in response to 3OC12-HSL may explain the decreased bacterial clearance observed in PON2-def mice following PAO1 infection.
- © 2013 by American Heart Association, Inc.