The neurotrophic hepatocyte growth factor induces protolerogenic human dendritic cells

Molnarfi, Nicolas; Benkhoucha, Mahdia; Juillard, Catherine; Bjarnadóttir, Kristbjörg; Lalive, Patrice H.

doi:10.1016/j.jneuroim.2013.12.004

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…To characterize this population of CD8-expressing c-Met in MOG-induced EAE, we first isolated them from the spleen and the CNS at the peak disease (day 14). Cells were further co-cultured with irradiated syngeneic splenocytes loaded with 20 μg/ml (MOG 35-55 , MOG 37-50 , or gp100 [25][26][27][28][29][30][31][32][33] for 48 h in the presence of 20 ng/ml of IL-2. After re-stimulation with MOG 35-55 , we observed no difference in granzyme B and IFNγ secretion between c-Met + and c-Met − CD8 + T cells (Fig.…”

Section: Increased Granzyme B From C-met + Cd8 + T Cells In Eaementioning

confidence: 99%

“…The hepatocyte growth factor (HGF)/c-Met axis modulates several inflammatory-mediated diseases by acting on a wide variety of cells [25], including in EAE [26,27]. Recent reports have stressed the multiple anti-inflammatory effects of HGF, including a Th2/Th3 bystander deviation with increased transforming growth factor (TGF)-β1 and interleukin (IL)-10 [28,29] and inhibition of Agpresenting cell (APC) function [26,28,30,31]. HGF may also contribute to the expansion of myeloid-derived suppressor cells, which are potent T cell suppressors [32].…”

Section: Introductionmentioning

confidence: 99%

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c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells

Benkhoucha

Senoner

Lalive

2020

J Neuroinflammation

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Background: CD8 + T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8 + T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. Here, we examined the role of c-Met-expressing CD8 + T cells by using a MOG 35-55 T cell-mediated EAE model. Methods: Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG) 35-55 in complete Freund's adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, and c-Met expression by CD8 was evaluated by flow cytometry and immunofluorescence. Molecular, cellular, and killing function analysis were performed by real-time PCR, ELISA, flow cytometry, and killing assay. Results: In the present study, we observed that a fraction of murine effector CD8 + T cells expressed c-Met receptor (c-Met + CD8 +) in an experimental autoimmune encephalitis (EAE) model. Phenotypic and functional analysis of c-Met + CD8 + T cells revealed that they recognize the encephalitogenic epitope myelin oligodendrocyte glycoprotein 37-50. We demonstrated that this T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of c-Met + CD8 + T cells in cell-mediated cytotoxicity reactions Conclusions: Altogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8 + T cell-mediated neuroinflammation.

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Section: Increased Granzyme B From C-met + Cd8 + T Cells In Eaementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells

Benkhoucha

Senoner

Lalive

2020

J Neuroinflammation

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“…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. Conceivably, HGF might impair immunogenic DC function through induction of IL-10 release by DCs [60,69], a cytokine known to exhibit inhibitory effect on DCs in an autocrine manner [85].…”

Section: Dendritic Cells (Dcs)mentioning

confidence: 99%

Hepatocyte growth factor: A regulator of inflammation and autoimmunity

Molnarfi

Benkhoucha

Funakoshi

et al. 2015

Autoimmunity Reviews

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113

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“…Normally, Hif-1α, which is abundant in inflammatory M1 macrophages but not in M2 macrophages ( Takeda et al, 2010 ), attenuates Treg development and activates IL-17-producing Teff (Th17) cells, which promotes neutrophilic inflammation. Hgf stimulates tolerogenic DCs and Tregs, decreases Th17 cells, and downregulates markers of T-cell activation, thereby conferring immunotolerance ( Benkhoucha et al, 2010 ; Molnarfi et al, 2013 ). Hif-1α and Hgf contribute to this important immunoregulatory balance not only in the placenta; but also, in the central nervous system (CNS; Benkhoucha et al, 2010 ; Dang et al, 2011 ).…”

Section: Effect Of Ho-1 Deficiency On Pregnancy Outcomesmentioning

confidence: 99%

Heme oxygenase and the immune system in normal and pathological pregnancies

et al. 2015

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Normal pregnancy is an immunotolerant state. Many factors, including environmental, socioeconomic, genetic, and immunologic changes by infection and/or other causes of inflammation, may contribute to inter-individual differences resulting in a normal or pathologic pregnancy. In particular, imbalances in the immune system can cause many pregnancy-related diseases, such as infertility, abortions, pre-eclampsia, and preterm labor, which result in maternal/fetal death, prematurity, or small-for-gestational age newborns. New findings imply that myeloid regulatory cells and regulatory T cells (Tregs) may mediate immunotolerance during normal pregnancy. Effector T cells (Teffs) have, in contrast, been implicated to cause adverse pregnancy outcomes. Furthermore, feto-maternal tolerance affects the developing fetus. It has been shown that the Treg/Teff balance affects litter size and adoptive transfer of pregnancy-induced Tregs can prevent fetal rejection in the mouse. Heme oxygenase-1 (HO-1) has a protective role in many conditions through its anti-inflammatory, anti-apoptotic, antioxidative, and anti-proliferative actions. HO-1 is highly expressed in the placenta and plays a role in angiogenesis and placental vascular development and in regulating vascular tone in pregnancy. In addition, HO-1 is a major regulator of immune homeostasis by mediating crosstalk between innate and adaptive immune systems. Moreover, HO-1 can inhibit inflammation-induced phenotypic maturation of immune effector cells and pro-inflammatory cytokine secretion and promote anti-inflammatory cytokine production. HO-1 may also be associated with T-cell activation and can limit immune-based tissue injury by promoting Treg suppression of effector responses. Thus, HO-1 and its byproducts may protect against pregnancy complications by its immunomodulatory effects, and the regulation of HO-1 or its downstream effects has the potential to prevent or treat pregnancy complications and prematurity.

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The neurotrophic hepatocyte growth factor induces protolerogenic human dendritic cells

Cited by 12 publications

References 27 publications

c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells

c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells

Hepatocyte growth factor: A regulator of inflammation and autoimmunity

Heme oxygenase and the immune system in normal and pathological pregnancies

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