title: Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice.
abstract: Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2(-/-) mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2(-/-) mice compared with WT mice. Alveolar macrophages from acid-injured Akt2(-/-) mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2(-/-) mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2(-/-) mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2(-/-) macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.
authors.affiliation: Department of Clinical Chemistry, University of Crete, Medical School, 71003 Heraklion, Greece;
authors.forename: Eleni
authors.initials: E
authors.lastname: Vergadi
authors.forename: Katerina
authors.initials: K
authors.lastname: Vaporidi
authors.forename: Emmanuel E
authors.initials: EE
authors.lastname: Theodorakis
authors.forename: Christina
authors.initials: C
authors.lastname: Doxaki
authors.forename: Eleni
authors.initials: E
authors.lastname: Lagoudaki
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Ieronymaki
authors.forename: Vassilia I
authors.initials: VI
authors.lastname: Alexaki
authors.forename: Mike
authors.initials: M
authors.lastname: Helms
authors.forename: Eumorfia
authors.initials: E
authors.lastname: Kondili
authors.forename: Birte
authors.initials: B
authors.lastname: Soennichsen
authors.forename: Efstathios N
authors.initials: EN
authors.lastname: Stathopoulos
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Margioris
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Georgopoulos
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C532623:Mirn155 microRNA, mouse; D051193:Toll-Like Receptors; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt