ArticleProceedings of the National Academy of Sciences of the United States of America2016
Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- Therapeutic potential of natural coumarins in autoimmune diseases with underlying mechanisms.Frontiers in immunology · 2024Pooled it
- Oral hymecromone decreases hyaluronan in human study participants.The Journal of clinical investigation · 2022Trial
- Extracellular matrix remodeling therapeutic strategies to tackle central nervous system diseases.Neural regeneration research · 2026Article
- Assembled Hyaluronic Acid Therapeutics for Targeting M1 Macrophages and Regulating Immune Homeostasis for Ulcerative Colitis Treatment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Naive CD4iScience · 2026Article
- Taking its TOLL: the role of toll-like receptor 4 in human health and disease, and its potential as a therapeutic target.Frontiers in immunology · 2026Review
- Hyaluronan Accumulates in Inflamed Lymph Nodes and Promotes B-Cell Activation.Proteoglycan research · 2025Article
- 4-Methylumbelliferone (4-MU) Improves Learning and Memory After Cerebral Ischemia/Reperfusion Injury in Rats.Behavioural neurology · 2025Article
- Beneficial Actions of 4-Methylumbelliferone in Type 1 Diabetes by Promoting β Cell Renewal and Inhibiting Dedifferentiation.Biomedicines · 2024Article
- Glycosaminoglycans' Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Review
- Biology of neurofibrosis with focus on multiple sclerosis.Frontiers in immunology · 2024Review
- Low oral dose of 4-methylumbelliferone reduces glial scar but is insufficient to induce functional recovery after spinal cord injury.Scientific reports · 2023Article
- 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
- TSG6 hyaluronan matrix remodeling dampens the inflammatory response during colitis.Matrix biology : journal of the International Society for Matrix Biology · 2023Article
- The Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?International journal of molecular sciences · 2023Review
- Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection.Matrix biology : journal of the International Society for Matrix Biology · 2023Review
- 4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing.International journal of molecular sciences · 2023Article
- Review
- 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
- Targeting UDP-α-d-glucose 6-dehydrogenase alters the CNS tumor immune microenvironment and inhibits glioblastoma growth.Genes & diseases · 2022Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3(+) regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.
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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.