Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Aerospace Medicine, Fourth Military Medical University, Xi'an, China.
JCI Insight. 2019 Mar 7;5(6):126939. doi: 10.1172/jci.insight.126939.
The mTOR pathway is central to most cells. How mTOR is activated in macrophages and 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 like 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.
mTOR 通路是大多数细胞的核心。巨噬细胞中 mTOR 如何被激活以及如何调节巨噬细胞生理机能仍知之甚少。肿瘤抑制因子卵泡抑素 (FLCN) 是 RagC/D 的 GAP，RagC/D 是 mTOR 的调节剂。我们在此表明，LPS 可强烈抑制巨噬细胞中的 FLCN，使转录因子 TFE3 易位到核内，导致溶酶体生物发生、细胞因子产生和对炎症信号的超敏反应。核内 TFE3 还激活了 RagD 的转录正向反馈回路，刺激了不依赖于 FLCN 的经典 mTOR 信号向 S6K 的传递，并增加了细胞增殖。因此，LPS 同时抑制了 TFE3 臂并激活了 mTOR 的 S6K 臂。在体内，缺乏髓系 FLCN 的小鼠显示出慢性巨噬细胞激活，导致深刻的组织细胞浸润和组织破坏，具有人类组织细胞综合征（如 Erdheim-Chester 病）的特征。因此，我们的数据确定了一个由 LPS 调节的髓系细胞中关键的 FLCN-mTOR-TFE3 轴，该轴平衡了 mTOR 的激活并抑制了先天免疫反应。
