MSP-RON Pathway: Potential Regulator of Inflammation and Innate Immunity

Huang, Lili; Fang, Xianyong; Shi, Danrong; Yao, Shu-Hao; Wu, Weifang; Fang, Qiang; Yao, Hang‐Ping

doi:10.3389/fimmu.2020.569082

Cited by 31 publications

(29 citation statements)

References 71 publications

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“…By biological network analysis, we identified several immune-related pathways that showed differential regulation in severe forms of COVID-19, including the (MSP)-RON pathway, Gβγ signalling, and nitric oxide (NO) signalling. MSP-RON signalling mediates systemic inflammatory responses and abnormalities in MSP-RON signalling can lead to onset of autoimmune disease [65]. Perhaps a more central mediator of the inflammatory response guiding the difference between mild and severe forms of COVID-19 identified by our study is Gβγ, which directly activates PI3Kγ and is involved in the recruitment of neutrophils to sites of inflammation.…”

Section: Discussionmentioning

confidence: 89%

3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

Hunter¹,

Koutsothanasi²,

Wilson³

et al. 2021

Preprint

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Human infection with the SARS-CoV-2 virus leads to coronavirus disease (COVID-19). A striking characteristic of COVID-19 infection in humans is the highly variable host response and the diverse clinical outcomes, ranging from clinically asymptomatic to severe immune reactions leading to hospitalization and death. Here we used a 3D genomic approach to analyse blood samples at the time of COVID diagnosis, from a global cohort of 80 COVID-19 patients, with different degrees of clinical disease outcomes. Using 3D whole genome EpiSwitch® arrays to generate over 1 million data points per patient, we identified a distinct and measurable set of differences in genomic organization at immune-related loci that demonstrated prognostic power at baseline to stratify patients with mild forms of illness and those with severe forms that required hospitalization and intensive care unit (ICU) support. Further analysis revealed both well established and new COVID-related dysregulated pathways and loci, including innate and adaptive immunity; ACE2; olfactory, Gβψ, Ca2+ and nitric oxide (NO) signalling; prostaglandin E2 (PGE2), the acute inflammatory cytokine CCL3, and the T-cell derived chemotactic cytokine CCL5. We identified potential therapeutic agents for mitigation of severe disease outcome, with several already being tested independently, including mTOR inhibitors (rapamycin and tacrolimus) and general immunosuppressants (dexamethasone and hydrocortisone). Machine learning algorithms based on established EpiSwitch® methodology further identified a subset of 3D genomic changes that could be used as prognostic molecular biomarker leads for the development of a COVID-19 disease severity test.

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Section: Discussionmentioning

confidence: 89%

3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

Hunter¹,

Koutsothanasi²,

Wilson³

et al. 2021

Preprint

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“…21,22 Many studies have focused on the role of the MSP-RON pathway in liver diseases. 22 In endotoxin-exposed mice, mice with selective Ron loss in hepatocytes exhibited less liver damage and increased survival compared with mice with Ron loss in macrophages, which suggested that targeted inhibition of the MSP-RON pathway could protect against acute liver injury. 23 Some studies have shown that the MSP-RON pathway can reduce liver fibrosis by inhibiting adipogenesis in a diet-induced nonalcoholic steatohepatitis mouse model.…”

Section: Introductionmentioning

confidence: 99%

“…Since MSP is mainly synthesised and secreted by hepatocytes, its receptor RON is mainly expressed in hepatocytes and Kupffer cells in the liver 20 . The MSP‐RON pathway participates in regulating liver homeostasis and regulating inflammation through the autocrine pathway of hepatocytes and the paracrine pathway of Kupffer cells 21,22 . Many studies have focused on the role of the MSP‐RON pathway in liver diseases 22 .…”

Section: Introductionmentioning

confidence: 99%

“…The MSP‐RON pathway participates in regulating liver homeostasis and regulating inflammation through the autocrine pathway of hepatocytes and the paracrine pathway of Kupffer cells 21,22 . Many studies have focused on the role of the MSP‐RON pathway in liver diseases 22 . In endotoxin‐exposed mice, mice with selective Ron loss in hepatocytes exhibited less liver damage and increased survival compared with mice with Ron loss in macrophages, which suggested that targeted inhibition of the MSP‐RON pathway could protect against acute liver injury 23 .…”

Section: Introductionmentioning

confidence: 99%

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The MSP‐RON pathway regulates liver fibrosis through transforming growth factor beta‐dependent epithelial–mesenchymal transition

Weng

Dong

Shi

et al. 2021

Liver International

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Background: Liver fibrosis is pathologically important in the liver cirrhosis progression. The epithelial-mesenchymal transition (EMT) is crucial for organ fibrosis.Macrophage-stimulating protein (MSP) and its receptor tyrosine kinase, RON, promote cellular EMT. However, their role in liver fibrosis is unclear. Here, we clarify the biological profile, potential mechanisms and therapeutic targets of the MSP-RON pathway in liver fibrosis. Materials and methods: Macrophage-stimulating protein expression and its correlation with clinicopathological characteristics of cirrhosis were evaluated in 57 clinical cases and a control group. The effect of MSP-RON pathway in liver fibrosis was determined in vitro and in vivo. The therapeutic effects of MSP or RON inhibition on liver fibrosis were evaluated in a mouse liver fibrosis model. Results: Macrophage-stimulating protein is upregulated in liver cirrhosis, which was associated with poor patient prognosis. The MSP-RON pathway promoted hepatocytes EMT. MSP-RON-induced EMT depends on the transforming growth factor beta (TGFβ) pathway and is regulated by TGFβ inhibitors. In animal models, an MSP blocking antibody and a small molecule inhibitor of RON, BMS-777607, both inhibited liver fibrosis progression. Conclusion: Our study revealed that MSP is an important biomarker in liver cirrhosis progression and can be used to prognose patients. The MSP-RON pathway promotes the EMT of hepatocytes and the progress of fibrosis via a TGFβ related pathway. Consequently, we identified a new treatment strategy for liver cirrhosis through targeted inhibition of MSP/RON. This research increases the understanding of EMTmodulated liver fibrosis and provides new insights into biomarkers and therapeutic targets of liver fibrosis.| 1957 WENG Et al.

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“…Recepteur d’origine nantais (RON, also known as MST1R) is a receptor in the tyrosine kinase receptor family of the MET family ( Huang et al, 2020 ). RON participates in epithelial cell proliferation and tissue repair ( Nanney et al, 1998 ), antagonizing LPS-induced inflammatory factor synthesis ( Laskin et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

RON Expression Mediates Lipopolysaccharide-Mediated Dendritic Cell Maturation via March-I

Huang

Fang

Zhang

et al. 2021

Front. Cell. Infect. Microbiol.

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The macrophage stimulating protein (MSP)–Recepteur d’origine nantais (RON) signaling pathway regulates macrophage function. Here, we verified RON receptor expression in bone marrow-derived dendritic cells (BMDCs) by real time-PCR, Western blot, and flow cytometry. Flow cytometry was used to detect the changes in MHC II and CD86 expression following the inhibition of RON in BMDCs and splenic dendritic cells (DCs). Immunoprecipitation and Western blot were used to detect the level of MHC II and CD86 ubiquitination. An enzyme-linked immunosorbent assay was used to detect cytokine release, and a mixed lymphocyte reaction was performed to evaluate DC maturity. The results show that the inhibition of RON leads to an increase in March-1 transcription, which intensifies the ubiquitination of MHC II and CD86 and ultimately leads to a decreased level of these two molecules. The mixed lymphocyte reaction provided evidence that RON inhibition decreased the ability of DCs to promote the proliferation of T cells. The MSP-RON signaling pathway may play an important role in lipopolysaccharide (LPS)-stimulated DC maturation through March-I and may protect DC differentiation following LPS stimulation.

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MSP-RON Pathway: Potential Regulator of Inflammation and Innate Immunity

Cited by 31 publications

References 71 publications

3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

The MSP‐RON pathway regulates liver fibrosis through transforming growth factor beta‐dependent epithelial–mesenchymal transition

RON Expression Mediates Lipopolysaccharide-Mediated Dendritic Cell Maturation via March-I

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