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.

Hepatocyte growth factor: A regulator of inflammation and autoimmunity

“…Similar results were reported for the emigration of cutaneous DCs (Langerhans cell, LCs) from the skin [63] or attraction of DCs within the thymus [82]. The importance of HGF in influencing murine immune responses was further powered by studies indicating that in addition to control the migratory process of DCs, HGF could impair murine DC activation [65,70] or confer them with suppressive activities such as the capacity to favor regulatory T cells (Tregs) induction [68,69,83]. Notably, increased DC expression of program-death ligand 1 and IL-27, potent signals for DC-mediated induction of Treg cells, were found to be up-regulated by HGF treatment [83].…”

“…The importance of HGF in influencing murine immune responses was further powered by studies indicating that in addition to control the migratory process of DCs, HGF could impair murine DC activation [65,70] or confer them with suppressive activities such as the capacity to favor regulatory T cells (Tregs) induction [68,69,83]. Notably, increased DC expression of program-death ligand 1 and IL-27, potent signals for DC-mediated induction of Treg cells, were found to be up-regulated by HGF treatment [83]. Likewise, human DCs differentiated in the presence of HGF were shown to adopt a protolerogenic phenotype with increased ability to generate regulatory T cells [60,84], a property that might be exploited therapeutically in T cell-mediated immune disorders.…”

Glucocorticoid-Induced Leucine Zipper Enhanced Expression in Dendritic Cells Is Sufficient To Drive Regulatory T Cells Expansion In Vivo

“…The GC-Induced Leucine Zipper protein (GILZ) is a GC-induced protein initially reported in dexamethasone (Dex)-treated thymocytes (6). We have previously shown ex vivo that the level of GILZ expression in human DCs controls their tolerance-inducing function (7)(8)(9) and extended to other hematopoietic cells these observations (10,11), which were confirmed by others (12)(13)(14)(15). GILZ expression is partly dependent on endogenous steroids in vivo (12), and its expression in DCs is enhanced in vitro by GC, IL-10, TGF-b (7,8), mitomycin C (16), rapamycin (15), vitamin D3 (15), and tumor environment (17 on DCs (8,9).…”

“…GILZ expression is partly dependent on endogenous steroids in vivo (12), and its expression in DCs is enhanced in vitro by GC, IL-10, TGF-b (7,8), mitomycin C (16), rapamycin (15), vitamin D3 (15), and tumor environment (17 on DCs (8,9). Downregulation of GILZ in DCs promotes the activation of effector CD4 + T cells (8,13,14,17). To gain insight into the impact of GILZ on the regulatory functions of DCs in vivo, we generated CD11c-GILZ hi transgenic mice.…”

Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice

“…13,[24][25][26][27] To determine whether GILZ is expressed in B lymphocytes, BM cells from WT mice were analyzed by qPCR for the expression of GILZ at various stages of B-cell development ( Figure 1A). We have found that GILZ is expressed in all B-cell developmental stages at levels comparable with those of CD4 1 CD25 -T cells, with the highest expression levels of GILZ mRNA detected in mature/recirculating IgM 1 IgD 1 B cells ( Figure 1A).…”