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.

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Acknowledgements

We thank U. Reichart and T. Kolbe for support in mouse breeding. We are grateful to D. Georg for the possibility of using the XYLON Maxishot. We would also like to thank M. Stadler and H. Dolznig (Medical University of Vienna) for providing human-monocyte-derived macrophages. Tsc1+/+ MEFs were a kind gift of D.J. Kwiatkowski (Harvard Medical School). T.W. is supported by grants from the Austrian Science Fund (FWF) grant FWF-P27701-B20, the Else-Kröner-Fresenius-Stiftung (P2013_A149), and the Herzfelder'sche Familienstiftung. M.L. is supported by the [DOC] Doctoral Fellowship Programme of the Austrian Academy of Sciences. V.S. is funded by FWF SFB F28 and SBF F47. M. Müller is funded by FWF SFB F28. M. Mikula is supported by the FWF grant P25336-B13.

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Affiliations

  1. Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.

    • Monika Linke
    • , Ha Thi Thanh Pham
    • , Karl Katholnig
    • , Thomas Schnöller
    • , Florian Demel
    • , Birgit Schütz
    • , Margit Rosner
    • , Boris Kovacic
    • , Nyamdelger Sukhbaatar
    • , Mario Mikula
    • , Markus Hengstschläger
    •  & Thomas Weichhart
  2. Department of Laboratory Medicine (KILM), Medical University of Vienna, Vienna, Austria.

    • Anne Miller
    •  & Arvand Haschemi
  3. Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

    • Birgit Niederreiter
    •  & Stephan Blüml
  4. Department of Radiation Oncology, Division of Medical Radiation Physics, Medical University of Vienna, Vienna, Austria.

    • Peter Kuess
  5. Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.

    • Veronika Sexl
  6. Biomodels Austria and Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.

    • Mathias Müller
  7. Department of Ecogenomics and Systems Biology and Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria.

    • Wolfram Weckwerth
  8. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.

    • Martin Susani
  9. Department of Human Genetics, Emory University, Atlanta, Georgia, USA.

    • Michael J Gambello

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Contributions

The study was conceived by M.L. and T.W. The research was carried out by M.L., H.T.T.P., K.K., T.S., A.M., F.D., B.S., M.R., B.K., N.S., B.N., P.K. and T.W. Resources were provided by S.B., V.S., M. Mikula, M. Müller, W.W., A.H., M.S., M.H., M.J.G. and T.W. T.W. wrote the original draft of the manuscript. All of the authors reviewed and edited the manuscript. The study was supervised by T.W.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas Weichhart.

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https://doi.org/10.1038/ni.3655

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