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

Summary 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).
Graphical Abstract
Highlights • mTOR regulates fibroblast-like synoviocyte inflammatory transcriptional programs • mTOR limits NF-κB signaling by enhancing IκB-α • mTOR shifts inflammation toward STAT1-dependent genes • mTOR couples amino acid sensing to TNF activation in fibroblast-like synoviocytes
Karonitsch et al. show that TNF signaling co-opts the mTOR pathway in fibroblast-like synoviocytes. mTOR activation is associated with decreased NF-κB-mediated but increased STAT1-dependent gene expression. Thus, the metabolic checkpoint kinase mTOR regulates the synovial tissue response to inflammation in rheumatoid arthritis (RA).