Inhibition of hyaluronan (HA) synthesis protects against CNS autoimmunity and increases CXCL12 expression in the inflamed CNS [Glycobiology and Extracellular Matrices]

June 27th, 2014 by Mueller, A. M., Yoon, B. H., Sadiq, S. A.

Hyaluronan may have proinflammatory roles in the context of CNS autoimmunity. It accumulates in demyelinated 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 receptor-2 and -4 to stimulate inflammatory gene expression. We assessed HA's role 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 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'CSF cells and in spinal cord tissue during EAE. Hyaluronan suppressed production of CXCL12, while 4MU increased spinal CXCL12 in naive animals and during neuroinflammation. Neutralization of CXCR4, the most prominent receptor of CXCL12, by administration of AMD3100 diminished 4MU's protective impact in atEAE. 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.
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