Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells

Benkhoucha, Mahdia; Molnarfi, Nicolas; Dunand-Sauthier, Isabelle; Merkler, Doron; Schneiter, Gregory; Bruscoli, Stefano; Riccardi, Carlo; Tabata, Yasuhiko; Funakoshi, Hiroshi; Nakamura, Toshikazu; Reith, Walter; Santiago-Raber, Marie-Laure; Lalive d'Epinay, Patrice

doi:10.4049/jimmunol.1302338

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Title		Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells
Authors		Benkhoucha, Mahdia Molnarfi, Nicolas Dunand-Sauthier, Isabelle Merkler, Doron Schneiter, Gregory Bruscoli, Stefano Riccardi, Carlo Tabata, Yasuhiko Funakoshi, Hiroshi Nakamura, Toshikazu Reith, Walter Santiago-Raber, Marie-Laure Lalive d'Epinay, Patrice show all authors [1 - 13]
Published in		The Journal of immunology. 2014, vol. 193, no. 6, p. 2743-52
Abstract		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-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions.
Identifiers		DOI: 10.4049/jimmunol.1302338 PMID: 25114100
Full text		Article (Accepted version) (1.5 MB) - Limited access to UNIGE
Structures		Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research groups		Groupe Reith Walter (pathologie et immunologie) (282) Groupe Santiago-Raber Marie-Laure (pathologie et immunologie) (915) Métastases du foie (657) Scléroses en plaques, neuroimmunologie, encéphalite autoimmune expérimentale (843)
Citation (ISO format)		BENKHOUCHA, Mahdia et al. Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells. In: The Journal of immunology, 2014, vol. 193, n° 6, p. 2743-52. doi: 10.4049/jimmunol.1302338 https://archive-ouverte.unige.ch/unige:42844