Journal Article

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

Rosner, Margit, Mikula, Mario, Katholnig, Karl, Demel, Florian, Kuess, Peter, Miller, Anne, Sexl, Veronika, Kovacic, Boris, Weckwerth, Wolfram, Hengstschläger, Markus, Gambello, Michael J, Pham, Ha Thi Thanh, Schnöller, Thomas, Sukhbaatar, Nyamdelger, Susani, Martin, Niederreiter, Birgit, Blüml, Stephan, Müller, Mathias, Linke, Monika, Weichhart, Thomas, Schütz, Birgit, Haschemi, Arvand

2017

Overview

Macrophages are critical for granuloma formation, but the cell-intrinsic mechanisms remain unknown. Weichhart and colleagues demonstrate that chronic mTOR activity leads to macrophage-dependent granuloma formation, which may have relevance to sarcoidosis. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/249 / 631/250/262 / 692/420/2780/262 / 692/699/249 / Animals / Biomedicine / Cell Line / Cyclin-Dependent Kinase 4 - metabolism / Development and progression / Disease Progression / Genes / Genetic aspects / Glucose metabolism / Granuloma / Granuloma - drug therapy / Granuloma - immunology / Health aspects / Humans / Hypertrophy / Immunology / Infectious Diseases / Macrophages / Macrophages - drug effects / Macrophages - immunology / Mechanistic Target of Rapamycin Complex 1 / Mice / Mice, Inbred C57BL / Mice, Knockout / Multiprotein Complexes - metabolism / Mycobacterium / Physiological aspects / Protein kinases / RNA, Small Interfering - genetics / Sarcoidosis / Sarcoidosis - drug therapy / Sarcoidosis - immunology / Signal Transduction / TOR Serine-Threonine Kinases - metabolism / Tuberculosis / Tuberous sclerosis / Tuberous Sclerosis Complex 2 Protein / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism