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Activation of MERTK­-signalling in monocytes/macrophages - a mechanism to explain susceptibility to infection in patients with cirrhosis and a future therapeutic target?

English title Activation of MERTK­-signalling in monocytes/macrophages - a mechanism to explain susceptibility to infection in patients with cirrhosis and a future therapeutic target?
Applicant Bernsmeier Christine
Number 159984
Funding scheme Project funding (Div. I-III)
Research institution Abt. für Gastroenterologie und Hepatologie Universitätsspital Basel
Institution of higher education Cantonal hospital of St.Gallen - KSPSG
Main discipline Immunology, Immunopathology
Start/End 01.10.2015 - 30.09.2019
Approved amount 400'008.00
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Keywords (6)

Cirrhosis; Infection susceptibility; MERTK signalling; Monocytes/macrophages; Innate immune response; Liver

Lay Summary (German)

Lead
Die Leberzirrhose ist eine häufige Erkrankung mit hoher Sterblichkeit. Patientinnen und Patienten erkranken und versterben meist an Infektionen. Welche Mechanismen die Infektabwehr schwächen, wird in diesem Projekt untersucht.
Lay summary

Inhalt und Ziele des Forschungsprojektes

Die Leberzirrhose tritt als Folge unterschiedlicher Lebererkrankungen auf. Durch die zunehmende Häufigkeit gewisser Lebererkrankungen und die alternde Gesellschaft nimmt auch die Häufigkeit der Leberzirrhose zu. Die hohe Sterblichkeit der Erkrankung ist interessanterweise nicht auf den Funktionsverlust der Leber selbst zurückzuführen, sondern meist auf zusätzliche Infektionen, die die Erkrankung entgleisen lassen. Warum Patientinnen und Patienten mit Leberzirrhose Infektionen nicht abwehren können, und diesen erliegen, ist weitgehend unbekannt.

In diesem Projekt wird auf molekularer Ebene die sogenannte „angeborene“ Immunantwort bei Leberzirrhose unterschiedlichen Schweregrades detailliert untersucht. Wir hoffen, feststellen zu können, wann und wodurch es zu einer Störung der körpereigenen Abwehr und damit zu einer Infektanfälligkeit kommt. Insbesondere werden wir einen Mechanismus, die MERTK-Signaltransduktion, aufschlüsseln, der die Abwehr durch Immunzellen hemmen kann, wie es beispielsweise für die Abwehr von Krebszellen bekannt ist. MERTK-Hemmstoffe zur Behandlung von Patientinnen und 
Patienten sind bereits entwickelt worden. Wir hoffen herauszufinden, ob diese Hemmstoffe theoretisch die Immunantwort auch bei Leberzirrhose verbessern und somit den Krankheitsverlauf mildern und die Sterblichkeit verringern könnten.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes

Für die Leberzirrhose stehen keine Behandlungsmöglichkeiten zur Verfügung ausser der Lebertransplantation, einem medizinisch und ethisch anspruchsvollen Verfahren. Daher ist es aus wünschenswert, Strategien zu entwickeln, die das Fortschreiten der Erkrankung verlangsamen, und das Überleben verlängern könnten. Ein genaues Verständnis der molekularen, pathophysiologischen Vorgänge ist dafür notwendig. Wir erhoffen uns, durch diese Erkenntnisse mögliche neue Therapieansätze für Patientinnen und Patienten mit Leberzirrhose definieren zu können.

Direct link to Lay Summary Last update: 15.04.2015

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis
Brenig Robert, Pop Oltin T, Triantafyllou Evangelos, Geng Anne, Singanayagam Arjuna, Perez-Shibayama Christian, Besse Lenka, Cupovic Jovana, Künzler Patrizia, Boldanova Tuyana, Brand Stephan, Semela David, Duong François HT, Weston Christopher J, Ludewig Burkhard, Heim Markus H, Wendon Julia, Antoniades Charalambos G, Bernsmeier Christine (2019), Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis, in Life Science Alliance, 3(1), e201900465-e201900465.
CD14 + CD15 − HLA-DR − myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure
Bernsmeier Christine, Triantafyllou Evangelos, Brenig Robert, Lebosse Fanny J, Singanayagam Arjuna, Patel Vishal C, Pop Oltin T, Khamri Wafa, Nathwani Rooshi, Tidswell Robert, Weston Christopher J, Adams David H, Thursz Mark R, Wendon Julia A, Antoniades Charalambos Gustav (2018), CD14 + CD15 − HLA-DR − myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure, in Gut, 67(6), 1155-1167.
Liver dendritic cells and NAFLD evolution: A remaining open issue
Bernsmeier Christine, Albano Emanuele (2017), Liver dendritic cells and NAFLD evolution: A remaining open issue, in Journal of Hepatology, 66(6), 1120-1122.

Collaboration

Group / person Country
Types of collaboration
Prof J Wendon/ Institute of Liver Studies/ King's College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr Dr D Semela/ Hepatology department and Liver Biology Laboratory/ Kantonsspital St. Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof MH Heim/ Hepatology department and laboratory/ University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr CG Antoniades/ Section of Hepatology St. Mary’s Hospital/ Imperial College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof B Ludewig/ Immunbiologie/ Medizinisches Forschungszentrum/ Kantonsspital St. Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr C Weston/ Centre for Liver & Gastro Research/ Institue of Immunology/ University of Birmingham Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Swiss Society of Gastroenterology (SGG-SSG), the Swiss Society of Visceral Surgery (SGVC-SSCV) and the Swiss Association for the Study of the Liver (SASL) 2019 Poster AXL-expressing immune-homeostatic liver macrophages disappear in progressive cirrhosis 12.09.2019 Interlaken, Switzerland Bernsmeier Christine; Brenig Robert;
Department of Biomedicine Summer Symposium 2019 Talk given at a conference AXL+-monocytes regulate innate immune responses in liver cirrhosis 21.08.2019 Basel, Switzerland Brenig Robert; Bernsmeier Christine;
18th Hepatobiliary and Gastrointestinal Research Retreat 2019 Talk given at a conference Distinct circulating monocytic subsets regulate innate immune responses in cirrhosis 11.01.2019 Les Diablerets, Switzerland Brenig Robert; Bernsmeier Christine;
18th Hepatobiliary and Gastrointestinal Research Retreat 2019 Talk given at a conference AXL-expressing immune-homeostatic liver macrophages disappear in patients with progression of cirrhosis 11.01.2019 Les Diablerets, Switzerland Bernsmeier Christine; Brenig Robert;
Gastro Regio Meeting 2018 Talk given at a conference AXL-expressing immunoregulatory monocytes indicate disease severity in patients with advanced cirrhosis 07.12.2018 Freiburg im Breisgau, Germany Bernsmeier Christine; Brenig Robert;
Annual Meeting of the Swiss Society of Gastroenterology (SGG-SSG), the Swiss Society of Visceral Surgery (SGVC-SSCV) and the Swiss Association for the Study of the Liver (SASL) 2018 Talk given at a conference AXL-expressing immunoregulatory monocytes indicate disease severity in patients with advanced cirrhosis 27.09.2018 Interlaken, Switzerland Brenig Robert; Bernsmeier Christine;
The International Liver Congress, EASL, 2018 Poster AXL-expressing monocytes indicate immuneparesis and disease severity in patients with cirrhosis 11.04.2018 Paris, France Bernsmeier Christine; Brenig Robert;
17th Hepatobiliary and Gastrointestinal Research Retreat 2018 Talk given at a conference AXL-expressing monocytes indicate immuneparesis and disease severity in patients with cirrhosis 12.01.2018 Les Diablerets, Switzerland Bernsmeier Christine; Brenig Robert;
16th Hepatobiliary and Gastrointestinal Research Retreat 2017 Talk given at a conference Regulation of differential TAM-receptor signalling on monocytes/macrophages in patients with cirrhosis – does it refer to endotoxin tolerance and infection susceptibility? 13.01.2017 Stoos, Switzerland Brenig Robert;


Awards

Title Year
Forschungs-Förderungspreis der Schweizerischen Gesellschaft für Gastroenterologie (SGG) 2017

Associated projects

Number Title Start Funding scheme
189072 Diversity and compartmentalisation of monocytes & macrophages and immuneparesis in patients with cirrhosis 01.01.2020 Project funding (Div. I-III)
164083 Flow cytometer for multiparametric analysis of rare cell populations 01.12.2015 R'EQUIP

Abstract

Cirrhosis of the liver is a condition with a high mortality and raising prevalence worldwide. Infectious complications are highly frequent and independent predictors of outcome in patients with cirrhosis - being the leading cause of decompensation, ‘acute-on-chronic’ liver failure (ACLF) and death. There is no treatment option other than transplantation, applicable at early stages and to only a minority of patients. Susceptibility to infection has been documented in patients with cirrhosis and has been attributed to immuneparesis and monocyte dysfunction in the state of decompensation and liver failure. The underlying mechanisms are incompletely understood. Development of targeted immunomodulatory strategies might effectively reduce infectious complications and mortality in cirrhosis.MER receptor tyrosine kinase (MERTK), expressed on monocytes/macrophages, plays a pivotal role in dampening innate immune responses. We have recently discovered and documented the role of MERTK in innate immune dysfunction in patients with ACLF. In ACLF monocytes/macrophages expressing MERTK are expanded in various compartments (the circulation, liver, extrahepatic tissues) where they dampen responses to microbial challenge. MERTK inhibitors have been developed and shown to improve innate immune responses of monocytes/macrophages in conditions such as lung injury and leucocyte anti-tumour response.The mechanisms of as to how MERTK signalling becomes activated in the progression from compensated to decompensated cirrhosis and impacts on response to microbial challenge are unexplored. Understanding the mechanism that underpins this pathophysiological process might enable development of a future targeted immunotherapy for patients with cirrhosis and offset infectious complications.We hypothesise that activation of the MERTK signalling pathway plays a pivotal role in suppression of monocyte/macrophage innate immune responses to microbial challenge in patients with cirrhosis, explains their susceptibility to infection and provides a novel immunotherapeutic target to reverse immuneparesis: We propose that (i) the innate immune response is progressively impaired with progression of cirrhosis from Child A to C in concert with the severity of portal hypertension, and that (ii) MERTK signalling is activated in parallel to progression of disease severity and innate immune dysfunction. The mechanism involves (iii) increasing bacterial translocation with progressive cirrhosis and portal hypertension, activation of toll-like receptor (TLR) signalling through bacterial products and (iv) increasing cytokine production from the progressively inflamed liver also serves to activate the MERTK signalling cascade.The primary aim of the project is to investigate innate immune suppression during the evolution of cirrhosis and following acute decompensation (AD) in parallel to the activation of MERTK signalling on circulatory monocytes and tissue macrophages of cirrhotic patients. The secondary aim is to decipher the molecular mechanism leading to MERTK activation as inhibitor of innate immune response, which will involve investigating the role of (a) gut-derived bacterial products on monocytes in-vitro and (b) inflammation of the liver and inflammatory cytokine production and its effect on tissue macrophages and monocytes ex-vivo. The tertiary aim is to evaluate the eligibility of MERTK inhibitors as future immunotherapeutic agents to prevent infectious complications.
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