Journal
CELL REPORTS
Volume 23, Issue 7, Pages 2157-2167Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.04.044
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Funding
- Austrian Academy of Sciences
- European Research Council [ERC AdG 250179 i-FIVE, ERC AdG 695214 GameofGates]
- Austrian Science Fund [FWF I2192-B22 ERASE, FWF F4711-B20 Myeloid Neoplasms]
- ERC [695214 GameofGates]
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Accumulating evidence suggests that metabolic-master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-kappa B-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA).
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