Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 6, Pages 2743-2752Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302338
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Funding
- Swiss National Science Foundation (SNF) [310030-132705, 310030-153164]
- Swiss Society for Multiple Sclerosis (SSMS
- European Committee for Treatment and Research in Multiple Sclerosis Foundation
- SNF [PP00P3-128372, 310030-138338, 3100A0-105895]
- SSMS
- Swiss National Science Foundation (SNF) [310030_153164, 310030_132705] Funding Source: Swiss National Science Foundation (SNF)
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Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference-directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene-deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-beta 1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions.
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