期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 5, 页码 1339-1344出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1525086113
关键词
hyaluronan; multiple sclerosis; T-cell polarization; T-cell trafficking; astrogliosis
资金
- NIH [NS069375, R01 DK096087-01, R01 HL113294-01A1, U01 AI101984, R01 GM110481]
- Stanford Shared FACS Facility
- Human Frontier Science Program Long Term Fellowship [LT830]
- California Institute for Regenerative Medicine Training Grant [TG2-01159]
- Stanford University Child Health Research Institute
- SPARK Program
- Juvenile Diabetes Research Foundation [3-PDF-2014-224-A-N]
- Building Interdisciplinary Research Team Supplement [AR037296]
- [U01 AI101990]
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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