Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Abstract

Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25 + Foxp3 + regulatory T (T reg ) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-γ and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T reg cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.cMet (HGF receptor) | experimental autoimmune encephalitis | immune tolerance | multiple sclerosis | neuroprotection

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

“…Originally identified as a mitogen for hepatocytes, HGF acts as a potent regulator in multiple animal models of immunemediated disorders (7)(8)(9)(10), which suggests that HGF regulates key inflammatory events that are common to many diseases and organ systems. In particular, HGF has been demonstrated to re-strain the Ag-presenting function of mouse DCs (7) and to govern the development of Treg cell-inducing regulatory DCs (11,12). We recently suggested that such a mechanism might account for the protective role of CNS-restricted overexpression of HGF in myelin oligodendrocyte glycoprotein (MOG)-induced EAE (11).…”

“…In particular, HGF has been demonstrated to re-strain the Ag-presenting function of mouse DCs (7) and to govern the development of Treg cell-inducing regulatory DCs (11,12). We recently suggested that such a mechanism might account for the protective role of CNS-restricted overexpression of HGF in myelin oligodendrocyte glycoprotein (MOG)-induced EAE (11). From an immunologic and therapeutic standpoint, it is important to understand the molecular basis involved in DC immunoregulation by HGF.…”

“…Cold EDTA was added to a final concentration of 20 mM, and cell suspensions were incubated for 5 min at room temperature before filtering through nylon mesh to remove tissue and cell aggregates. Highly pure splenic DCs were subsequently positively selected using anti-mouse CD11c colloidal superparamagnetic microbeads (Miltenyi Biotec), as reported previously (11). The purity of CD4 + and CD11c + cells, confirmed by flow cytometry, was routinely .95 and .85%, respectively.…”

Antibody response in MOG35–55 induced EAE

“…Mice were kept under pathogen-free conditions and used at 8-10 weeks of age. For active immunization, B6 females were immunized with MOG 35-55 (100 μg) as described (Benkhoucha et al, 2010). Animals received pertussis toxin (300 ng per mouse) on days 0 and 2 after immunization.…”

“…Animals received pertussis toxin (300 ng per mouse) on days 0 and 2 after immunization. Mice were assigned clinical scores daily from 0 to 5 (Benkhoucha et al, 2010). Mice were bled at day 0 (before immunization) and days 7, 14 and 21 after immunization.…”