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

Abstract

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. Here we show that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of 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 mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 towards 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.

The PI3K Pathway in Human Disease

“…In addition, p110δ has an isoform-specific role in LPS responses by promoting internalization of TLR4 and dissociation of the adaptor protein TIRAP (Aksoy et al, 2012). Interestingly, hyperactivation of mTORC1 signaling in macrophages lacking TSC2 suppresses NFκB function and drives metabolic reprogramming, loss of quiescence, and macrophage proliferation leading to formation of granulomas (Linke et al, 2017). …”

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

“…Inhibition of mTORC1 with rapamycin promotes proinflammatory cytokine production while inhibiting IL-10 production, whereas mTORC1 activation due to TSC2 deletion in monocytes results in enhanced production of IL-10 and diminished production of proinflammatory cytokines in response to LPS (Chen et al, 2012; Mercalli et al, 2013; Weichhart et al, 2008). Recent work has shown that chronic mTORC1 signaling in macrophages due to TSC2 deletion promotes macrophage hypertrophy and proliferation, leading to excessive granuloma formation in vivo (Linke et al, 2017), indicating that excessive mTORC1 activity in macrophages can promote immunopathology.…”

mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages

“…mTORC1 and mTORC2 signaling play different and selective roles in guiding T cell differentiation (Delgoffe et al, 2011; Heikamp et al, 2014; Pollizzi et al, 2015). Likewise, recent work has demonstrated the importance of mTOR in activation and polarization in monocyte-derived macrophages (Ai et al, 2014; Byles et al, 2013; Festuccia et al, 2014; Hallowell et al, 2017; Huang et al, 2016; Jiang et al, 2014; Linke et al, 2017; Pan et al, 2012; Weichhart et al, 2008; Zhu et al, 2014). In this report, we demonstrate a critical role for mTORC2 in regulating peritoneal ResMφ differentiation, metabolic reprogramming and function.…”