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

Cell Reports
Thomas KaronitschGiulio Superti-Furga

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).

Citations

Oct 26, 2018·Clinical and Experimental Immunology·U FearonJ M Fletcher
May 24, 2019·Immunotherapy·Chrysoula StathopoulouGeorge Bertsias
Jan 3, 2020·Current Opinion in Rheumatology·Brandon Wyman, Andras Perl
May 16, 2019·Neural Regeneration Research·Baruh PolisAbraham O Samson
Aug 2, 2019·Clinical Microbiology Reviews·Juarez Antonio Simões Quaresma
May 21, 2020·Frontiers in Medicine·Blaž BurjaMojca Frank-Bertoncelj
Aug 17, 2020·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Wei-Wei CaiFang Wei
Jan 27, 2019·Laboratory Investigation; a Journal of Technical Methods and Pathology·Bernhard BrandstetterThomas Karonitsch
Oct 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Christopher BiancoIan Mohr
Jan 1, 2021·Ageing Research Reviews·Linli ZhengAli Mobasheri
Feb 23, 2020·Osteoarthritis and Cartilage·K SunF Guo
Nov 26, 2020·Ophthalmic Plastic and Reconstructive Surgery·Jonathan C P RoosRachna Murthy
Jul 27, 2021·The Journal of Pathology·Long JiaoThorsten Cramer

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Methods Mentioned

BETA
ELISA
confocal microscopy
transfection
electron cryomicroscopy

Software Mentioned

CellProfiler
Easy Microarray Analysis
Interferome
Bioconductor
GraphPad Prism
R
SAM

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