Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression
- Author(s)
- Monika Linke, Ha Thi Thanh Pham, Karl Katholnig, Thomas Schnoelller, Anne Miller, Florian Demel, Birgit Schuetz, Margit Rosner, Boris Kovacic, Nyamdelger Sukhbaatar, Birgit Niederreiter, Stephan Blueml, Peter Kuess, Veronika Sexl, Mathias Mueller, Mario Mikula, Wolfram Weckwerth, Arvand Haschemi, Martin Susani, Markus Hengstschlaeger, Michael J. Gambello, Thomas Weichhart
- 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-κ B 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.
- Organisation(s)
- Research Platform Vienna Metabolomics Center
- External organisation(s)
- Medizinische Universität Wien, Veterinärmedizinische Universität Wien, Emory University
- Journal
- Nature Immunology
- Volume
- 18
- Pages
- 293-302
- No. of pages
- 10
- ISSN
- 1529-2908
- DOI
- https://doi.org/10.1038/ni.3655
- Publication date
- 03-2017
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301902 Immunology, 301303 Medical biochemistry
- Keywords
- ASJC Scopus subject areas
- Immunology and Allergy, Immunology
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/chronic-signaling-via-the-metabolic-checkpoint-kinase-mtorc1-induces-macrophage-granuloma-formation-and-marks-sarcoidosis-progression(463b8ca6-2b59-48ca-8ef4-92f55c544c5b).html