ArticleAnnals of the rheumatic diseases2018
Methotrexate limits inflammation through an A20-dependent cross-tolerance mechanism.
Article in Annals of the rheumatic diseases, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 50 citations in OpenAlex.
- Monocytes from inflammatory arthritis patients accumulate methotrexate and their transcriptome predicts methotrexate clinical response.Cellular and molecular life sciences : CMLS · 2026Article
- From Bench to Clinic: Advances in Anti-Inflammatory Therapies for Atherosclerotic Coronary Artery Disease.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Review
- The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation.Nature communications · 2025Article
- Comprehensive analysis of genes associated with necroptosis and pyroptosis in intestinal ischemia-reperfusion injury.PloS one · 2025Article
- Article
- Multiscale, mechanistic model of Rheumatoid Arthritis to enable decision making in late stage drug development.NPJ systems biology and applications · 2024Article
- Combination of Methotrexate and Resveratrol Reduces Pro-Inflammatory Chemokines in Human THP-1 Cells.Journal of inflammation research · 2024Article
- Innate immune memory in inflammatory arthritis.Nature reviews. Rheumatology · 2023Review
- Evaluation ofMolecular imaging and biology · 2023Article
- Methotrexate Provokes Disparate Folate Metabolism Gene Expression and Alternative Splicing in Ex Vivo Monocytes and GM-CSF- and M-CSF-Polarized Macrophages.International journal of molecular sciences · 2023Article
- From Bench to Bedside in Rheumatoid Arthritis from the "2022 GISEA International Symposium".Journal of clinical medicine · 2023Review
- The actions of methotrexate on endothelial cells are dependent on the shear stress-induced regulation of one carbon metabolism.Frontiers in immunology · 2023Article
- Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory responseFrontiers in immunology · 2023Article
- GeneticInternational journal of molecular sciences · 2022Article
- Repolarization of Unbalanced Macrophages: Unmet Medical Need in Chronic Inflammation and Cancer.International journal of molecular sciences · 2022Review
- Activation of LXR Nuclear Receptors Impairs the Anti-Inflammatory Gene and Functional Profile of M-CSF-Dependent Human Monocyte-Derived Macrophages.Frontiers in immunology · 2022Article
- Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.Frontiers in immunology · 2022Article
- Targeting Toll-like Receptor (TLR) Pathways in Inflammatory Arthritis: Two Better Than One?Biomolecules · 2021Review
- Signals and Mechanisms Regulating Monocyte and Macrophage Activation in the Pathogenesis of Juvenile Idiopathic Arthritis.International journal of molecular sciences · 2021Review
- The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis.Frontiers in immunology · 2021Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivesMethotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis (RA), but the mechanism of its anti-inflammatory action is not fully understood. In RA, macrophages display a proinflammatory polarisation profile that resembles granulocyte-macrophage colony-stimulating factor (GM-CSF)-differentiated macrophages and the response to MTX is only observed in thymidylate synthase
methodsIntracellular responses to TLR ligands, TNFα or RASF stimulation in long-term low-dose MTX-exposed human macrophages were determined through quantitative real-time PCR, western blot, ELISA and siRNA-mediated knockdown approaches. The role of MTX in vivo was assessed in patients with arthritis under MTX monotherapy and in a murine sepsis model.
resultsMTX conditioned macrophages towards a tolerant state, diminishing interleukin (IL)-6 and IL-1β production in LPS, LTA, TNFα or RASF-challenged macrophages. MTX attenuated LPS-induced MAPK and NF-κB activation, and toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF1)-dependent signalling. Conversely, MTX increased the expression of the NF-κB suppressor A20 (
conclusionsMTX impairs macrophage proinflammatory responses through upregulation of A20 expression. The A20-mediated MTX-induced innate tolerance might limit inflammation in the RA synovial context, and positions A20 as a potential MTX-response biomarker.
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