title: Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells.
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.
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Unit of Neuroimmunology and Multiple Sclerosis, Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, 1211 Geneva, Switzerland;
authors.forename: Mahdia
authors.initials: M
authors.lastname: Benkhoucha
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Unit of Neuroimmunology and Multiple Sclerosis, Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, 1211 Geneva, Switzerland;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland; Institut für Neuropathologie, Universitätsmedizin Göttingen, Georg-August-Universität, 37099 Göttingen, Germany;
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Unit of Neuroimmunology and Multiple Sclerosis, Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, 1211 Geneva, Switzerland;
authors.forename: Gregory
authors.initials: G
authors.lastname: Schneiter
authors.affiliation: Section of Pharmacology, Department of Medicine, University of Perugia, 06132 Perugia, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.affiliation: Section of Pharmacology, Department of Medicine, University of Perugia, 06132 Perugia, Italy;
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.affiliation: Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa 078-8510, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.affiliation: Neurogen Inc., Nakahozumi, Ibaraki, Osaka 567-0034, Japan; and.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland;
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland;
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Santiago-Raber
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Unit of Neuroimmunology and Multiple Sclerosis, Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, 1211 Geneva, Switzerland; Division of Laboratory Medicine, Department of Genetic and Laboratory Medicine, Geneva University Hospital, 1211 Geneva, Switzerland patrice.lalive@hcuge.ch.
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology; D003345:Corticosterone / Q000097:blood / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000494:pharmacology*; D007108:Immune Tolerance / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000276:immunology
chemical_list: C498608:Dsip1 protein, mouse; C553307:HGF protein, mouse; C556062:IL10 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor; D003345:Corticosterone