Abstract
Hyaluronan (HA) may have proinflammatory roles in the context of CNS autoimmunity. It accumulates in demyelinated multiple sclerosis (MS) lesions, promotes antigen presentation, and enhances T-cell activation and proliferation. HA facilitates lymphocyte binding to vessels and CNS infiltration at the CNS vascular endothelium. Furthermore, HA signals through Toll-like receptors 2 and 4 to stimulate inflammatory gene expression. We assessed the role of HA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS by administration of 4-methylumbelliferone (4MU), a well established inhibitor of HA synthesis. 4MU decreased hyaluronan synthesis in vitro and in vivo. It was protective in active EAE of C57Bl/6 mice, decreased spinal inflammatory infiltrates and spinal infiltration of Th1 cells, and increased differentiation of regulatory T-cells. In adoptive transfer EAE, feeding of 4MU to donor mice significantly decreased the encephalitogenicity of lymph node cells. The transfer of proteolipid protein (PLP)-stimulated lymph node cells to 4MU-fed mice resulted in a delayed EAE onset and delayed spinal T-cell infiltration. Expression of CXCL12, an anti-inflammatory chemokine, is reduced in MS patients in CSF cells and in spinal cord tissue during EAE. Hyaluronan suppressed production of CXCL12, whereas 4MU increased spinal CXCL12 in naive animals and during neuroinflammation. Neutralization of CXCR4, the most prominent receptor of CXCL12, by administration of AMD3100 diminished the protective impact of 4MU in adoptive transfer EAE. In conclusion, hyaluronan exacerbates CNS autoimmunity, enhances encephalitogenic T-cell responses, and suppresses the protective chemokine CXCL12 in CNS tissue. Inhibition of hyaluronan synthesis with 4MU protects against an animal model of MS and may represent an important therapeutic option in MS and other neuroinflammatory diseases.
Highlights
Hyaluronan accumulates in chronic demyelinated multiple sclerosis (MS) lesions
We addressed the influence of 4MU feeding on generation of Th1 and Th17 cells as well as their infiltration into spinal cord tissue during active myelin oligodendrocyte glycoprotein (MOG) peptide EAE in C57Bl/6 mice
Animals were sacrificed on day 20 after active EAE induction, and CD4ϩ T-cells in inguinal lymph nodes and spinal cord tissue were analyzed by flow cytometry. 4MU did not modulate Th1 but decreased Th17 cell numbers in inguinal lymph nodes, suggesting that 4MU interfered with differentiation or stimulation of encephalitogenic T-cells
Summary
Results: 4-Methylumbelliferone (4MU) inhibits HA synthesis, is protective in active and passive MS models, modulates T-cell responses, and prevents CXCL12 suppression within inflamed and non-inflamed CNS tissue. Hyaluronan (HA) may have proinflammatory roles in the context of CNS autoimmunity It accumulates in demyelinated multiple sclerosis (MS) lesions, promotes antigen presentation, and enhances T-cell activation and proliferation. We assessed the role of HA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS by administration of 4-methylumbelliferone (4MU), a well established inhibitor of HA synthesis. Hyaluronan exacerbates CNS autoimmunity, enhances encephalitogenic T-cell responses, and suppresses the protective chemokine CXCL12 in CNS tissue.
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