title: Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization.
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.
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; hkuipers@stanford.edu steinman@stanford.edu.
authors.forename: Hedwich F
authors.initials: HF
authors.lastname: Kuipers
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Mary
authors.initials: M
authors.lastname: Rieck
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305;
authors.forename: Irina
authors.initials: I
authors.lastname: Gurevich
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Nadine
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305;
authors.forename: Manish J
authors.identifier: http://orcid.org/0000-0002-4490-5595
authors.initials: MJ
authors.lastname: Butte
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.affiliation: Matrix Biology Program, Benaroya Research Institute, Seattle, WA 98101.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; hkuipers@stanford.edu steinman@stanford.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bollyky
mesh_terms: D000818:Animals; D016764:Cell Polarity; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006923:Hymecromone / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006923:Hymecromone; D006820:Hyaluronic Acid
keywords: T-cell polarization; T-cell trafficking; astrogliosis; hyaluronan; multiple sclerosis