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Nat Immunol. 2017 Mar;18(3):293-302. doi: 10.1038/ni.3655. Epub 2017 Jan 16.

Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.

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Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
Department of Laboratory Medicine (KILM), Medical University of Vienna, Vienna, Austria.
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Department of Radiation Oncology, Division of Medical Radiation Physics, Medical University of Vienna, Vienna, Austria.
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.
Biomodels Austria and Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Department of Ecogenomics and Systems Biology and Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria.
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Department of Human Genetics, Emory University, Atlanta, Georgia, USA.


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.

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