title: Role of PON2 in innate immune response in an acute infection model.
abstract: N-(3-oxododecanoyl)-l-homoserine lactone (3OC(12)-HSL) is a quorum-sensing molecule produced by gram-negative microbial pathogens such as Pseudomonas aeruginosa (PAO1). 3OC(12)-HSL is involved in the regulation of bacterial virulence factors and also alters the function of the host immune cells. Others and we have previously shown that paraoxonase 2 (PON2), a member of the paraoxonase gene family expressed in immune cells, hydrolyzes 3OC(12)-HSL. In this study, we examined i) whether macrophage PON2 participates in 3OC(12)-HSL hydrolysis, ii) the effect of PON2 deficiency in acute PAO1 infection in mice and iii) the effect of 3OC(12)-HSL on PON2 deficient (PON2-def) macrophages. When compared to wild type macrophages, both intact cells and membrane-enriched protein lysates obtained from PON2-def macrophages show a marked impairment in their ability to hydrolyze 3OC(12)-HSL. PON2 expression (message and protein) is not altered in response to 3OC(12)-HSL in macrophages. 3OC(12)-HSL treated PON2-def macrophages showed i) an increase in ER stress and oxidative stress, ii) defective phosphatidylinositol 3-kinase (PI3 kinase)/AKT activation, and iii) reduced phagocytosis function. Moreover, the nitration to phosphorylation ratio of Tyr458 in p85 protein, the regulatory subunit of PI3-kinase that has been correlated with the phagocytosis function of macrophages, was increased in PON2-def macrophages. Antioxidant treatment reversed the effects of PON2 deficiency in macrophage phagocytosis function. Furthermore, following administration of 1.6 × 10(7) CFU of PAO1, bacterial clearance was significantly reduced in the lungs (5.7 fold), liver (2.5 fold), and spleen (14.8 fold) of PON2-def mice when compared to wild type mice. Our results suggest that PON2 plays an important role in innate immune defense against PAO1 infection.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California Los Angeles, CA 90095, USA.
authors.forename: Asokan
authors.initials: A
authors.lastname: Devarajan
authors.forename: Noam
authors.initials: N
authors.lastname: Bourquard
authors.forename: Victor R
authors.initials: VR
authors.lastname: Grijalva
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ekambaram
authors.initials: E
authors.lastname: Ganapathy
authors.forename: Jitendra
authors.initials: J
authors.lastname: Verma
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D043303:Aryldialkylphosphatase / Q000235:genetics*; D006714:Homoserine / Q000031:analogs & derivatives / Q000494:pharmacology; D007113:Immunity, Innate / Q000235:genetics*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011552:Pseudomonas Infections / Q000235:genetics* / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D053038:Quorum Sensing / Q000276:immunology; D017382:Reactive Oxygen Species
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; C109860:N-(3-oxododecanoyl)homoserine lactone; D017382:Reactive Oxygen Species; D006714:Homoserine; C578990:PON2 protein, mouse; D043303:Aryldialkylphosphatase; D015107:4-Butyrolactone
keywords: 3OC(12)-HSL; AHL; Acyl homo serine lactones; CFU; Colony forming units; DCF; Dichlorofluorescein; ER; Endoplasmic reticulum; Endoplasmic reticulum stress; Mitochondrial oxidative stress; N-(3-oxododecanoyl)-l-homoserine lactone; PAO1; PI3 kinase; PON2-def; Paraoxonase 2; Paraoxonase 2-deficiency; Phosphatidylinositol 3-kinase; Pseudomonas aeruginosa; Quorum sensing
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