Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

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 inhibito...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-02, Vol.113 (5), p.1339-1344
Main Authors: Kuipers, Hedwich F., Rieck, Mary, Gurevich, Irina, Nagy, Nadine, Butte, Manish J., Negrin, Robert S., Wight, Thomas N., Steinman, Lawrence, Bollyky, Paul L.
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Brain
Cell Polarity
Experiments
Hyaluronic Acid - antagonists & inhibitors
Hyaluronic Acid - biosynthesis
Hymecromone - pharmacology
Lymphocyte Activation
Lymphocytes
Matrix
Mice
Mice, Inbred C57BL
Pathogenesis
Polarization
Rodents
T-Lymphocytes - immunology
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1525086113