title: TREM-2 promotes macrophage-mediated eradication of Pseudomonas aeruginosa via a PI3K/Akt pathway.
abstract: Triggering receptor expressed on myeloid cells 2 (TREM-2) is a cell surface receptor abundantly expressed on myeloid lineage cells such as macrophages and dendritic cells. It is reported that TREM-2 functions as an inflammatory inhibitor in macrophages and dendritic cells. However, the role of TREM-2 in bacterial killing remains unclear. This study explored the role of TREM-2 in bacterial eradication of Pseudomonas aeruginosa (PA), a Gram-negative bacterium which causes various opportunistic infections. Phagocytosis assay assessed by flow cytometry suggested that TREM-2 was not involved in the uptake of PA by macrophages, while bacterial plate count data showed that TREM-2 was required for macrophage-mediated intracellular killing of PA. Moreover, our results demonstrated that TREM-2 promoted macrophage killing by enhancing reactive oxygen species (ROS), but not nitric oxygen (NO) production. Treatment with N-acetylcysteine, a ROS scavenger, diminished the TREM-2-mediated intracellular killing of PA. To further investigate the underlined mechanisms of TREM-2-promoted bacterial killing, we examined the activation of downstream mitogen-activated protein kinases and PI3K/Akt pathway. Western blot data showed that silencing of TREM-2 inhibited phosphorylation of Akt, but not ERK, JNK or P38. In addition, pretreatment with PI3K active product PIP3 DiC16 reversed the elevation of intracellular bacterial load in TREM-2-silenced macrophages, while PI3K inhibitor wortmannin restored the decline of bacterial load in TREM-2-overexpressed macrophages. These data together suggested that the TREM-2-mediated bacterial killing is dependent on the activation of PI3K/Akt signalling, which may provide a better understanding of the host antibacterial immune defence.
authors.affiliation: Department of Immunology, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Diseases Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: M
authors.initials: M
authors.lastname: Wu
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010587:Phagocytosis / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000111:Acetylcysteine; D000730:Androstadienes; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C498716:Trem2 protein, mouse