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Activation and metabolism status of macrophages in metabolic disease and potential impact of tyrosine kinase inhibitors (TKIs)

Applicant Cavelti-Weder Claudia
Number 180472
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.09.2018 - 31.08.2019
Approved amount 248'851.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Endocrinology

Keywords (4)

Non-alcoholic fatty liver disease (NAFLD); Macrophages; Tyrosine kinase inhibitor; Metabolic disease

Lay Summary (German)

Lead
Übergewicht führt zu sogenannter “nicht-alkoholischer Leberverfettung“ (NAFLD), bei deren Entstehung Makrophagen eine Schlüsselrolle spielen. Das Ziel unserer Studie war zu untersuchen, ob eine Dämpfung der Makrophagen-Aktivität zu einer Verbesserung von Leberverfettung führt.
Lay summary
Dabei untersuchten wir das Medikament Imatinib, welches für chronisch myeloische Leukämien zugelassen ist. In der Literatur wurde bereits eine anti-entzündliche Wirkung von Imatinib beschrieben. Zuerst behandelten wir Makrophagen mit Imatinib in vitro, was zu einer Dämpfung der Makrophagen Aktivität führte. Als nächsten Schritt behandelten wir übergewichtige Mäuse mit Imatinib und fanden, dass dadurch Makrophagen in ihrer Aktivierung gedämpft werden und die Leberverfettung abnimmt. Als letztes haben wir menschliche Monozyten – aus denen sich Makrophagen entwickeln – mit Imatinib behandelt. Wie im Mausmodell reduzierte sich ebenfalls deren Aktivierung.

Unser Ziel ist es, durch die immunmodulierende Wirkung von Medikamenten den erhöhten Entzündungszustand, wie er bei Übergewicht vorkommt, zu dämpfen und die Auswirkungen auf Folgekomplikationen von Übergewicht, wie beispielsweise die Leberverfettung, zu untersuchen. Nebst einem besseren Verständnis über die Entstehung der Krankheit wird dies den Weg zur Entwicklung von immunmodulierenden Therapien bei metabolischen Erkrankungen ebnen.
Direct link to Lay Summary Last update: 09.09.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver
AlAsfoor Shefaa, Rohm Theresa V., Bosch Angela J. T., Dervos Thomas, Calabrese Diego, Matter Matthias S., Weber Achim, Cavelti-Weder Claudia (2018), Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver, in Scientific Reports, 8(1), 15331-15331.

Collaboration

Group / person Country
Types of collaboration
Dr. Matthias Matter,Gastroint. Pathologie, Leberpathologie, Molekularpathologie, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Achim Weber, Experimental and Molecular Pathology, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Markus Heim, Hepatology Lab, University of Basel Switzerland (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
Novartis seminar Individual talk Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and the liver 11.01.2019 Basel, Switzerland Cavelti-Weder Claudia;


Associated projects

Number Title Start Funding scheme
161135 Activation and metabolism status of macrophages in metabolic disease and potential impact of tyrosine kinase inhibitors (TKIs) 01.09.2015 Ambizione

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases worldwide. As macrophages play a key role in NAFLD, therapies targeting macrophages have been postulated. Indeed, strategies depleting macrophages or blocking monocyte recruitment into the liver improve NAFLD, however, are not feasible in clinical practice. As an alternative to macrophage depletion, our goal was to assess whether macrophage attenuation can be achieved as an immune-modulatory treatment in metabolic disease and whether this improves NAFLD. We tested imatinib as a potential immune-modulatory drug, which is an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties. Murine macrophages were polarized in vitro to different activation states in the presence or absence of imatinib (aim 1); mice on high fat diet orally treated with imatinib or vehicle (aim 2); and human monocytes of diabetic patients and healthy controls treated with or without imatinib for translational application (aim 3). Indeed, imatinib specifically attenuated pro-inflammatory murine macrophages in vitro and in vivo. In livers of obese mice, imatinib caused Kupffer cells to adopt an attenuated phenotype via modulation of the TNFa-pathway. This immune-modulation resulted in markedly improved hepatic steatosis along with beneficial effects on liver function, lipids and systemic inflammation. The immune-dampening effect of imatinib also prevailed in human monocytes, indicating translational applicability. Our study serves as a proof-of-principle that attenuation of macrophages as exemplified by imatinib improves NAFLD and may thus serve as a novel therapeutic strategy in patients with NAFLD. These findings possess great potential as due to the obesity epidemic the incidence of NAFLD is increasing dramatically, while no effective therapy besides weight loss exists. However, some questions remain open, such as whether imatinib is able to reduce also more advanced stages of NAFLD such as liver fibrosis (aim 4) or what mechanistic pathways are targeted by imatinib (aim 5). A more profound understanding of the role of macrophage attenuation in NAFLD and the molecular pathways involved will help in the development of new treatment strategies. The long-term goal would be to translate our findings to human NAFLD.
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