ArticleLife sciences2021
IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts.
Article in Life sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 32 citations in OpenAlex.
- Gut microbiota and immunometabolism in obesity.Gut microbes · 2026Review
- MMP3C v2: a network-based framework decoding metabolic plasticity in rheumatoid arthritis, enabling accurate diagnosis and uncovering cell-type-specific metabolic rewiring.Briefings in bioinformatics · 2026Article
- Tofacitinib repairs inflammation and mitochondrial dysregulation in GM-CSF-reprogrammed RA macrophages.Cellular & molecular immunology · 2026Article
- Irf7 aggravates prostatitis by promoting Hif-1α-mediated glycolysis to facilitate M1 polarization.Cellular and molecular life sciences : CMLS · 2025Article
- Enhancing the effectiveness of immunotherapy in rheumatoid arthritis by delaying immunosenescence triggered by fibroblast-like synoviocytes.Journal of orthopaedic surgery and research · 2025Review
- The Role and Mechanism of Protein Post‑Translational Modification in Rheumatoid Arthritis.Journal of inflammation research · 2025Review
- Modulation of IRAK4 as a therapeutic strategy against monosodium urate- and xanthine-induced inflammation in macrophages and HepG2 cells.Frontiers in immunology · 2025Article
- Interferon regulatory factor 5: a potential target for therapeutic intervention in inflammatory diseases.Frontiers in immunology · 2025Review
- Metabolic reprogramming: the central mechanism driving inflammatory polarization in rheumatoid arthritis and the regulatory role of traditional Chinese medicine.Frontiers in immunology · 2025Review
- Methotrexate promotes the release of granulocyte-macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling.Arthritis research & therapy · 2024Article
- New molecular targets in the treatment of rheumatoid arthritis.Current opinion in rheumatology · 2024Review
- Targeting TLR Signaling Cascades in Systemic Lupus Erythematosus and Rheumatoid Arthritis: An Update.Biomedicines · 2024Article
- Overview of mechanisms and novel therapies on rheumatoid arthritis from a cellular perspective.Frontiers in immunology · 2024Review
- Multi-omics profiling of collagen-induced arthritis mouse model reveals early metabolic dysregulation via SIRT1 axis.Scientific reports · 2022Article
- Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming.Cellular and molecular life sciences : CMLS · 2022Article
- Glycolysis in Innate Immune Cells Contributes to Autoimmunity.Frontiers in immunology · 2022Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Recent studies show a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (MΦs) and fibroblasts (FLS). Yet, it is unclear which pathways could be targeted to rebalance RA MΦs and FLS metabolic reprogramming. To identify novel targets that could normalize RA metabolic reprogramming, TLR7-mediated immunometabolism was characterized in RA MΦs, FLS and experimental arthritis. We uncovered that GLUT1, HIF1α, cMYC, LDHA and lactate were responsible for the TLR7-potentiated metabolic rewiring in RA MΦs and FLS, which was negated by IRAK4i. While in RA FLS, HK2 was uniquely expanded by TLR7 and negated by IRAK4i. Conversely, TLR7-driven hypermetabolism, non-oxidative PPP (CARKL) and oxidative phosphorylation (PPARγ) were narrowly dysregulated in TLR7-activated RA MΦs and FLS and was reversed by IRAK4i. Consistently, IRAK4i therapy disrupted arthritis mediated by miR-Let7b/TLR7 along with impairing a broad-range of glycolytic intermediates, GLUT1, HIF1α, cMYC, HK2, PFKFB3, PKM2, PDK1 and RAPTOR. Notably, inhibition of the mutually upregulated glycolytic metabolites, HIF1α and cMYC, was capable of mitigating TLR7-induced inflammatory imprint in RA MΦs and FLS. In keeping with IRAK4i, treatment with HIF1i and cMYCi intercepted TLR7-enhanced IRF5 and IRF7 in RA MΦs, distinct from RA FLS. Interestingly, in RA MΦs and FLS, IRAK4i counteracted TLR7-induced CARKL reduction in line with HIF1i. Whereas, cMYCi in concordance with IRAK4i, overturned oxidative phosphorylation via PPARγ in TLR7-activated RA MΦs and FLS. The blockade of IRAK4 and its interconnected intermediates can rebalance the metabolic malfunction by obstructing glycolytic and inflammatory phenotypes in RA MΦs and FLS.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.