HGF/Met-Signaling Contributes to Immune Regulation by Modulating Tolerogenic and Motogenic Properties of  Dendritic Cells

Hübel, Jessica; Hieronymus, Thomas

doi:10.3390/biomedicines3010138

Cited by 27 publications

(30 citation statements)

References 62 publications

(96 reference statements)

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“…Constitutive Met expression is limited to hematopoietic progenitor cells and their antigen-presenting progenies, including B cells, monocytes/macrophages, and DCs ( 29 , 44 ). However, exposure to pro-inflammatory cytokines leads to induction and/or upregulation of Met expression in various cell types, again pointing toward the regulatory link of tissue injury to the inflammatory response.…”

Section: The Immunoregulatory Function Of Hgf/met Signalingmentioning

confidence: 99%

The Impact of the Epithelial–Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration

Sagi

Hieronymus

2018

Front. Immunol.

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Langerhans cells (LCs), the epidermal dendritic cell (DC) subset, express the transmembrane tyrosine kinase receptor Met also known as hepatocyte growth factor (HGF) receptor. HGF is the exclusive ligand of Met and upon binding executes mitogenic, morphogenic, and motogenic activities to various cells. HGF exerts anti-inflammatory activities via Met signaling and was found to regulate various functions of immune cells, including differentiation and maturation, cytokine production, cellular migration and adhesion, and T cell effector function. It has only recently become evident that a number of HGF-regulated functions in inflammatory processes and immune responses are imparted via DCs. However, the mechanisms by which Met signaling in DCs conveys its immunoregulatory effects have not yet been fully understood. In this review, we focus on the current knowledge of Met signaling in DCs with particular attention on the morphogenic and motogenic activities. Met signaling was shown to promote DC mobility by regulating matrix metalloproteinase activities and adhesion. This is a striking resemblance to the role of Met in regulating a cell fate program during embryonic development, wound healing, and in tumor invasion known as epithelial–mesenchymal transition (EMT). Hence, we propose the concept that an EMT program is executed by Met signaling in LCs.

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Section: The Immunoregulatory Function Of Hgf/met Signalingmentioning

confidence: 99%

The Impact of the Epithelial–Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration

Sagi

Hieronymus

2018

Front. Immunol.

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“…More recently a subpopulation of CD8 positive cytotoxic T-cell has been found to express MET, further linking its pathway to a role in tumor immunity [20]. Moreover, HGF has been linked to increased expression of PD-L1 in dendritic cells and CTLA-4 in T-cells, with a role in the induction of immune tolerance [6,21].…”

Section: Discussionmentioning

confidence: 99%

“…The pleiotropic effect of the HGF/MET signaling pathway include also a role in modulation of the immune response, including involvement in dendritic cell function [6] and neutrophilic antitumoral response [7]. This function has been postulated to be involved in the potential acquisition of resistance to immunotherapy treatments [6].…”

Section: Introductionmentioning

confidence: 99%

Correlation of MET and PD-L1 expression in malignant melanoma

Song

Desar

Pengo

et al. 2020

Preprint

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Background: The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, PD-L1, with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. Methods: We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions; we then performed the same analysis in a human melanoma tissue microarray (TMA) containing 100 melanocytic lesions, including 42 cutaneous malignant melanomas, 20 mucosal melanoma, 21 metastatic melanomas and 17 benign melanocytic nevi as controls. After color deconvolution, TMA cores were identified and segmented to isolate staining and calculate the percentage of positive cells in each core. Results: Overall, MET expression was higher in metastatic lesions and it was higher in tumors with increased PD-L1 expression. Moreover, a positive correlation between MET and PD-L1 expression was found in metastatic melanoma. Conclusions: These data suggest that testing for expression of these markers should be conducted in patients with melanoma with metastatic disease and selective therapies targeting these proteins should be considered for advanced disease.

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“…The infiltration of immune cells is one of the characteristic differences between simple steatosis and the more severe steatohepatitis. Recent investigations describe an immunoregulatory function of c-Met on hematopoietic progenitor cells [ 51 , 52 ]. Further studies additionally show the expression of c-Met also on neutrophils and CD8 + T cells upon proinflammatory cytokine exposure during tissue injury [ 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

c‐Met Signaling Protects from Nonalcoholic Steatohepatitis‐ (NASH‐) Induced Fibrosis in Different Liver Cell Types

Drescher

Schumacher

Schenker

et al. 2018

Oxidative Medicine and Cellular Longevity

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Nonalcoholic steatohepatitis (NASH) is the most common chronic, progressive liver disease in Western countries. The significance of cellular interactions of the HGF/c-Met axis in different liver cell subtypes and its relation to the oxidative stress response remains unclear so far. Hence, the present study is aimed at investigating the role of c-Met and the interaction with the oxidative stress response during NASH development in mice and humans. Conditional c-Met knockout (KO) lines (LysCre for Kupffer cells/macrophages, GFAPCre for α-SMA+ and CK19+ cells and MxCre for bone marrow-derived immune cells) were fed chow and either methionine-choline-deficient diet (MCD) for 4 weeks or high-fat diet (HFD) for 24 weeks. Mice lacking c-Met either in Kupffer cells, α-SMA+ and CK19+ cells, or bone marrow-derived immune cells displayed earlier and faster progressing steatohepatitis during dietary treatments. Severe fatty liver degeneration and histomorphological changes were accompanied by an increased infiltration of immune cells and a significant upregulation of inflammatory cytokine expression reflecting an earlier initiation of steatohepatitis development. In addition, animals with a cell-type-specific deletion of c-Met exhibited a strong generation of reactive oxygen species (ROS) by dihydroethidium (hydroethidine) (DHE) staining showing a significant increase in the oxidative stress response especially in LysCre/c-Metmut and MxCre/c-Metmut animals. All these changes finally lead to earlier and stronger fibrosis progression with strong accumulation of collagen within liver tissue of mice deficient for c-Met in different liver cell types. The HGF/c-Met signaling pathway prevents from steatosis development and has a protective function in the progression to steatohepatitis and fibrosis. It conveys an antifibrotic role independent on which cell type c-Met is missing (Kupffer cells/macrophages, α-SMA+ and CK19+ cells, or bone marrow-derived immune cells). These results highlight a global protective capacity of c-Met in NASH development and progression.

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HGF/Met-Signaling Contributes to Immune Regulation by Modulating Tolerogenic and Motogenic Properties of Dendritic Cells

Cited by 27 publications

References 62 publications

The Impact of the Epithelial–Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration

The Impact of the Epithelial–Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration

Correlation of MET and PD-L1 expression in malignant melanoma

c‐Met Signaling Protects from Nonalcoholic Steatohepatitis‐ (NASH‐) Induced Fibrosis in Different Liver Cell Types

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