title: PTEN limits alveolar macrophage function against Pseudomonas aeruginosa after bone marrow transplantation.
abstract: Hematopoietic stem cell transplant patients are susceptible to infection despite cellular reconstitution. In a murine model of syngeneic bone marrow transplantation (BMT), we previously reported that BMT mice have impaired host defense against Pseudomonas aeruginosa pneumonia due to overproduction of (PG)E(2) in lung. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an effector in the PGE(2) signaling pathway that negatively regulates alveolar macrophage (AM) phagocytosis and bacterial killing. Therefore, examined whether overproduction of PGE(2) after BMT inhibits AM host defense by up-regulating PTEN phosphatase activity. We found that PTEN activity is elevated in BMT AMs in response to increased PGE(2) signaling and that pharmacological inhibition of PTEN activity in BMT AMs fully restores phagocytosis of serum-opsonized P. aeruginosa but only partially restores phagocytosis of nonopsonized P. aeruginosa. In wild-type mice transplanted with myeloid-specific conditional PTEN knockout (PTEN CKO) bone marrow, bacterial clearance is improved after challenge with P. aeruginosa pneumonia. Furthermore, PTEN CKO BMT AMs display improved TNF-α production and enhanced phagocytosis and killing of serum-opsonized P. aeruginosa despite overproduction of PGE(2). However, AM phagocytosis of nonopsonized P. aeruginosa is only partially restored in the absence of PTEN after BMT. This may be related to elevated AM expression of IL-1 receptor-associated kinase (IRAK)-M, a molecule previously identified in the PGE(2) signaling pathway to inhibit AM phagocytosis of nonopsonized bacteria. These data suggest that PGE(2) signaling up-regulates IRAK-M independently of PTEN and that these molecules differentially inhibit opsonized and nonopsonized phagocytosis of P. aeruginosa.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, USA. bmoore@umich.edu
authors.forename: Leah L N
authors.initials: LL
authors.lastname: Hubbard
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015232:Dinoprostone / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009942:Organometallic Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000276:immunology; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; C119540:oxodiperoxo(pyridine-2-carboxylate)vanadate(V); D053592:Interleukin-1 Receptor-Associated Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D015232:Dinoprostone; D007213:Indomethacin