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Myeloid folliculin balances mTOR activation to maintain innate immunity homeostasis
Jia Li, … , Edward M. Behrens, Zoltan Arany
Jia Li, … , Edward M. Behrens, Zoltan Arany
Published March 21, 2019; First published March 7, 2019
Citation Information: JCI Insight. 2019;4(6):e126939. https://doi.org/10.1172/jci.insight.126939.
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Categories: Research Article Cell biology Immunology

Myeloid folliculin balances mTOR activation to maintain innate immunity homeostasis

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Abstract

The mTOR pathway is central to most cells. How mTOR is activated in macrophages and how it modulates macrophage physiology remain poorly understood. The tumor suppressor folliculin (FLCN) is a GAP for RagC/D, a regulator of mTOR. We show here that LPS potently suppresses FLCN in macrophages, allowing nuclear translocation of the transcription factor TFE3, leading to lysosome biogenesis, cytokine production, and hypersensitivity to inflammatory signals. Nuclear TFE3 additionally activates a transcriptional RagD-positive feedback loop that stimulates FLCN-independent canonical mTOR signaling to S6K and increases cellular proliferation. LPS thus simultaneously suppresses the TFE3 arm and activates the S6K arm of mTOR. In vivo, mice lacking myeloid FLCN reveal chronic macrophage activation, leading to profound histiocytic infiltration and tissue disruption, with hallmarks of human histiocytic syndromes, such as Erdheim-Chester disease. Our data thus identify a critical FLCN-mTOR-TFE3 axis in myeloid cells, modulated by LPS, that balances mTOR activation and curbs innate immune responses.

Authors

Jia Li, Shogo Wada, Lehn K. Weaver, Chhanda Biswas, Edward M. Behrens, Zoltan Arany

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Figure 5

Loss of FLCN in monocyte lineage leads to expansion of peripheral monocyte progenitors via TFE3.

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Loss of FLCN in monocyte lineage leads to expansion of peripheral monocy...
(A–C) Progenitor and mature cell counting by FACS in spleens, livers, and bone marrow isolated from 12-week-old FLCNlox/lox, FLCNlox/lox Lyz2 Cre, and FLCNlox/lox Lyz2 Cre TFE3 KO mice. Values are represented as mean ± SEM from 3–6 animals per group. *P < 0.05, **P < 0.01 vs. FLCNlox/lox, #P < 0.05 vs. FLCNlox/lox Lyz2 Cre, determined by 1-way ANOVA followed by t test (Bonferroni correction). (D) Spleen weight/body weight (percentage) and liver weight/body weight (percentage) were calculated from 6 animals for each genotype at 12 weeks of age. Data are represented as mean ± SEM. **P < 0.01 vs. FLCNlox/lox, #P < 0.05 vs. FLCNlox/lox Lyz2 Cre, determined by 1-way ANOVA followed by t test (Bonferroni correction). (E) H&E staining of spleens from 8-week-old FLCNlox/lox and FLCNlox/lox Lyz2 Cre mice. Scale bar: 200 μm.
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