| Autor: |
Linke, Monika, Pham, Ha Thi Thanh, Katholnig, Karl, Schnöller, Thomas, Miller, Anne, Demel, Florian, Schütz, Birgit, Rosner, Margit, Kovacic, Boris, Sukhbaatar, Nyamdelger, Niederreiter, Birgit, Blüml, Stephan, Kuess, Peter, Sexl, Veronika, Müller, Mathias, Mikula, Mario, Weckwerth, Wolfram, Haschemi, Arvand, Susani, Martin, Hengstschläger, Markus, Gambello, Michael J, Weichhart, Thomas |
| Zdroj: |
Nature Immunology; February 2017, Vol. 18 Issue: 3 p293-302, 10p |
| Abstrakt: |
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. |
| Databáze: |
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