Inhibition of hyaluronan synthesis protects against central nervous system (CNS) autoimmunity and increases CXCL12 expression in the inflamed CNS.

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.

Cerebrospinal hepatocyte growth factor levels correlate negatively with disease activity in multiple sclerosis.

The hepatocyte growth factor (HGF) is a pleiotropic cytokine with neuroprotective and anti-inflammatory properties. Additionally, it enhances axonal outgrowth and oligodendroglial maturation. We studied the expression of HGF by cells derived from cerebrospinal fluid (CSF), quantified HGF in CSF samples and investigated the glial expression of HGF in vitro. We found decreased expression of HGF in CSF cells as well as reduced CSF but not plasma HGF protein levels in MS. MS patients with active disease had lower HGF CSF levels than inactive MS patients, and treatment with Natalizumab correlated with increased CSF concentration of HGF. In vitro, glial production of HGF was reduced by CSF from MS patients in comparison with CSF from controls. CSF levels of CCL2, a known inducer of HGF, also correlated strongly with HGF levels. We conclude that the expression of HGF within the CNS is reflective of disease activity in MS and this may be due to decreased induction of HGF by CCL2. Furthermore, the decreased HGF associated with active disease may potentially contribute to reduced stimulation for remyelination and the occurrence of shadow plaques frequently seen in MS patients. Our results merit further validation to establish whether CSF HGF is a biomarker for MS disease activity.

Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis.

BACKGROUND: The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown METHODS: To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-ß. RESULTS: The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-ß and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. In vitro, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25(hi) CD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-ß to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation. CONCLUSION: In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.