title: Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.
abstract: The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Linke
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Ha Thi Thanh
authors.initials: HT
authors.lastname: Pham
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Katholnig
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schnöller
authors.affiliation: Department of Laboratory Medicine (KILM), Medical University of Vienna, Vienna, Austria.
authors.forename: Anne
authors.initials: A
authors.lastname: Miller
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Demel
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schütz
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Margit
authors.initials: M
authors.lastname: Rosner
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Boris
authors.initials: B
authors.lastname: Kovacic
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Nyamdelger
authors.initials: N
authors.lastname: Sukhbaatar
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederreiter
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Stephan
authors.identifier: 0000-0002-2758-4400
authors.initials: S
authors.lastname: Blüml
authors.affiliation: Department of Radiation Oncology, Division of Medical Radiation Physics, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Kuess
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Biomodels Austria and Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Mikula
authors.affiliation: Department of Ecogenomics and Systems Biology and Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Weckwerth
authors.affiliation: Department of Laboratory Medicine (KILM), Medical University of Vienna, Vienna, Austria.
authors.forename: Arvand
authors.initials: A
authors.lastname: Haschemi
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Susani
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Hengstschläger
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.affiliation: Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.identifier: 0000-0002-4349-0797
authors.initials: T
authors.lastname: Weichhart
mesh_terms: D000818:Animals; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D018450:Disease Progression; D006099:Granuloma / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012507:Sarcoidosis / Q000188:drug therapy / Q000276:immunology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051358:Cyclin-Dependent Kinase 4