mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation

Cell Rep. 2018 May 15;23(7):2157-2167. doi: 10.1016/j.celrep.2018.04.044.

Abstract

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-κB-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).

Keywords: SLC38A9; amino acids; fibroblast-like synoviocytes; mechanistic target of rapamycin; nuclear factor ‘kappa-light-chain-enhancer’ of activated B cells; rheumatoid arthritis; signal transducer and activator of transcription 1; tumor necrosis factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Arthritis, Rheumatoid / pathology
  • Cellular Microenvironment*
  • Fibroblasts / pathology*
  • Gene Expression Regulation
  • Humans
  • Inflammation / pathology*
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / metabolism
  • Reproducibility of Results
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Synoviocytes / metabolism*
  • Synoviocytes / pathology*
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amino Acids
  • NF-kappa B
  • STAT1 Transcription Factor
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • TOR Serine-Threonine Kinases