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Inhibition of hyaluronan synthesis protects against central nervous system (CNS) autoimmunity and increases CXCL12 expression in the inflamed CNS.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2014 Aug 15; Vol. 289 (33), pp. 22888-22899. Date of Electronic Publication: 2014 Jun 27. - Publication Year :
- 2014
-
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.<br /> (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Adoptive Transfer
Animals
Anti-HIV Agents pharmacology
Benzylamines
Central Nervous System metabolism
Chemokine CXCL12 biosynthesis
Cyclams
Encephalomyelitis, Autoimmune, Experimental metabolism
Encephalomyelitis, Autoimmune, Experimental pathology
Female
Gene Expression Regulation drug effects
Heterocyclic Compounds pharmacology
Hyaluronic Acid biosynthesis
Inflammation immunology
Inflammation metabolism
Inflammation pathology
Mice
Rats
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
T-Lymphocytes, Regulatory pathology
Th1 Cells immunology
Th1 Cells metabolism
Th1 Cells pathology
Central Nervous System immunology
Chemokine CXCL12 immunology
Encephalomyelitis, Autoimmune, Experimental immunology
Gene Expression Regulation immunology
Hyaluronic Acid immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 289
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24973214
- Full Text :
- https://doi.org/10.1074/jbc.M114.559583