Dataset Information


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

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-?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.


PROVIDER: S-EPMC5321578 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

Similar Datasets

| GSE77075 | GEO
2020-01-01 | S-EPMC7531023 | BioStudies
2020-01-01 | S-EPMC7235403 | BioStudies
2020-01-01 | S-EPMC7003064 | BioStudies
2019-01-01 | S-EPMC6348723 | BioStudies
1000-01-01 | S-EPMC2822973 | BioStudies
2019-01-01 | S-EPMC6797840 | BioStudies
2019-01-01 | S-EPMC6958389 | BioStudies
1000-01-01 | S-EPMC5460893 | BioStudies
2017-01-01 | S-EPMC5650085 | BioStudies