title: Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses.
abstract: The activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN(-/-) macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBPβ and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity.
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Emine
authors.initials: E
authors.lastname: Sahin
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Stefan
authors.initials: S
authors.lastname: Haubenwallner
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Mario
authors.initials: M
authors.lastname: Kuttke
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Isabella
authors.initials: I
authors.lastname: Kollmann
authors.affiliation: St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;
authors.forename: Angela
authors.initials: A
authors.lastname: Halfmann
authors.affiliation: St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Dohnal
authors.affiliation: St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Dohnal
authors.affiliation: Bio Cancer Treatment International Ltd., Hong Kong, China;
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Bio Cancer Treatment International Ltd., Hong Kong, China;
authors.forename: Paul
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Bastian
authors.initials: B
authors.lastname: Hoesel
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, A-1090 Vienna, Austria; and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Einwallner
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Julia
authors.initials: J
authors.lastname: Brunner
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Julia B
authors.initials: JB
authors.lastname: Kral
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Waltraud C
authors.initials: WC
authors.lastname: Schrottmaier
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thell
authors.affiliation: Department of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Saferding
authors.affiliation: Department of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria; gernot.schabbauer@meduniwien.ac.at.
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D005838:Genotype; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D001119:Arginase; D022782:CCAAT-Enhancer-Binding Protein-beta; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C545013:Cebpb protein, mouse; C556062:IL10 protein, mouse; C494087:Stat3 protein, mouse; C487757:Pten protein, mouse; C544448:Arg1 protein, mouse