ArticleThe Journal of clinical investigation2015
Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Therapeutic potential of natural coumarins in autoimmune diseases with underlying mechanisms.Frontiers in immunology · 2024Pooled it
- Randomised, placebo-controlled trial of oral hymecromone in adults with pulmonary hypertension.Thorax · 2025Trial
- Oral hymecromone decreases hyaluronan in human study participants.The Journal of clinical investigation · 2022Trial
- Hyaluronan induces ERK activation with minimal transcriptomic changes in pancreatic α-cells.Biochemistry and biophysics reports · 2026Article
- Hyaluronan Accumulates in Inflamed Lymph Nodes and Promotes B-Cell Activation.Proteoglycan research · 2025Article
- Hyaluronan provokes inflammation but suppresses phagocytotic function in macrophages.Journal of molecular and cellular cardiology · 2025Article
- Beneficial Actions of 4-Methylumbelliferone in Type 1 Diabetes by Promoting β Cell Renewal and Inhibiting Dedifferentiation.Biomedicines · 2024Article
- Article
- Proteogenomic analysis integrated with electronic health records data reveals disease-associated variants in Black Americans.The Journal of clinical investigation · 2024Article
- Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention.iScience · 2024Article
- Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes.Matrix biology : journal of the International Society for Matrix Biology · 2023Article
- The pathogenic "symphony" in type 1 diabetes: A disorder of the immune system, β cells, and exocrine pancreas.Cell metabolism · 2023Review
- Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection.Matrix biology : journal of the International Society for Matrix Biology · 2023Review
- Hyaluronan in the Cancer Cells Microenvironment.Cancers · 2023Review
- 4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing.International journal of molecular sciences · 2023Article
- Importance of Heparan Sulfate Proteoglycans in Pancreatic Islets and β-Cells.International journal of molecular sciences · 2022Review
- Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections.JCI insight · 2022Article
- Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro.Matrix biology plus · 2022Article
- Biochemical, Biophysical, and Immunological Characterization of Respiratory Secretions in Severe SARS-CoV-2 (COVID-19) Infections.medRxiv : the preprint server for health sciences · 2022Article
- Modulation of hyaluronan signaling as a therapeutic target in human disease.Pharmacology & therapeutics · 2022Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.
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Registered trials
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.