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Molecular mechanisms of lipid-induced vascular inflammation in atherosclerosis

Applicant Freigang Stefan
Number 152872
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.01.2015 - 30.06.2018
Approved amount 510'890.00
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Keywords (5)

atherosclerosis; inflammation; lipids; interleukin-1; metabolism

Lay Summary (German)

Lead
Herz-Kreislauf-Erkrankungen sind die häufigste Todesursache weltweit. Obwohl diätetische und pharmakologische Interventionen derzeit verwendet werden, um die Hauptrisikofaktoren der Krankheit zu behandeln, gibt es bisher keine wirksamen Therapieansätze, die direkt den zugrundeliegenden Entzündungsprozess hemmen. Dieses Projekt untersucht einen neuen molekularen Mechanismus, über den Fettsäuren die Entzündungsreaktion in der Gefässwand fördern.
Lay summary

Inhalt und Ziele des Forschungsprojekts    

Metabolische Dysfunktion und chronische Entzündung verstärken sich gegenseitig in der Pathogenese von metabolischen Erkrankungen, wie der Arteriosklerose. Die molekularen Mechanismen, die diesen metabolisch-immunologischen Cross-talk vermitteln, sind nur unvollständig bekannt. Wir haben einen bisher unbekannten regulatorischen Mechanismus entdeckt, der metabolischen Stress mit der chronischen vaskulären Entzündung verbindet. Unsere Studie identifizierte die von Fettsäuren ausgelöste respiratorische Entkopplung der Mitochondrien als das metabolische Signal, welches die Produktion von Interleukin-1alpha auslöst. Wir planen daher die Bedeutung der physiologischen respiratorischen Entkopplung in Makrophagen für die vaskuläre Entzündung und Arteriosklerose sowie im Rahmen von anti-mikrobiellen Immunantworten zu untersuchen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit der Grundlagenforschung. Die chronische metabolische Entzündung ist ein wichtiger ätiologischer Faktor in der Pathogenese der Arteriosklerose. Die verfügbaren therapeutischen Optionen, diese Entzündung zu beeinflussen, sind sehr begrenzt. Ein besseres Verständnis der zugrunde liegenden immunologischen Mechanismen bildet eine wichtige Voraussetzung für die Entwicklung von neuen therapeutischen Ansätzen.

 

 

Direct link to Lay Summary Last update: 03.12.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential
Keller Christian W, Freigang Stefan, Lünemann Jan D (2017), Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential, in Frontiers in Immunology, 1-13.
The autophagy machinery restrains iNKT cell activation through CD1D1 internalization
Keller CW, Loi M, Ewert S, Quast I, Theiler R, Gannagé M, Münz C, De Libero G, Lünemann JD, Freigang S (2017), The autophagy machinery restrains iNKT cell activation through CD1D1 internalization, in Autophagy, 13(6), 1-12.
Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation.
Friedli Olivier, Freigang Stefan (2017), Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation., in Biochim Biophys Acta, 1862(4), 382-392.
The regulation of inflammation by oxidized phospholipids.
Freigang Stefan (2016), The regulation of inflammation by oxidized phospholipids., in Eur J Immunol, 46(8), 1818-1825.
TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis
Zysset Daniel, Weber Benjamin, Rihs Silvia, Brasseit Jennifer, Freigang Stefan, Riether Carsten, Banz Yara, Cerwenka Adelheid, Simillion Cedric, Marques-Vidal Pedro, Ochsenbein Adrian F, Saurer Leslie, Mueller Christoph (2016), TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis, in Nature Communications, 7, 13151.
Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.
Bretscher Peter, Egger Julian, Shamshiev Abdijapar, Trötzmüller Martin, Köfeler Harald, Carreira Erick M, Kopf Manfred, Freigang Stefan (2015), Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2., in EMBO Molecular Medicine, (5), 593-607.
T cell lipid peroxidation induces ferroptosis and prevents immunity to infection.
Matsushita Mai, Freigang Stefan, Schneider Christoph, Conrad Marcus, Bornkamm Georg W, Kopf Manfred (2015), T cell lipid peroxidation induces ferroptosis and prevents immunity to infection., in J Exp Med, 212(4), 555-568.
Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12.
Egger Julian, Fischer Stefan, Bretscher Peter, Freigang Stefan, Kopf Manfred, Carreira Erik M (2015), Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12., in Org Lett, 17(17), 4340-4343.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual meeting of the Swiss Society of Allergology and Immunology (SSAI) 2018 Poster Mitochondrial uncoupling in the regulation of T cell function 30.08.2018 Interlaken, Switzerland Friedli Olivier; Freigang Stefan;
International Summer School 2018 Talk given at a conference Immune recognition of lipids in inflammation and immunopathology 29.07.2018 Interlaken, Switzerland Freigang Stefan;
International Summer School 2018 Poster Impact of Oxidized Phospholipid Signaling on Macrophage Differentiation and Functionality in Health and Disease 29.07.2018 Interlaken, Switzerland Baumgartner Johanna;
Annual meeting of the Swiss Society of Pneumonology 2018 Talk given at a conference Unravelling protective signaling pathways in acute lung injury using a novel lung-on-chip technology 23.05.2018 St. Gallen, Switzerland Freigang Stefan;
Current concepts in Cancer biology - Tumor immunology – Inflammation Poster UCP2 – a mitochondrial regulator of T cell activation? 02.05.2018 Kandersteg, Switzerland Friedli Olivier;
Current concepts in Cancer biology - Tumor immunology – Inflammation Talk given at a conference Impact of Oxidized Phospholipid Signaling on Macrophage Differentiation and Functionality in Health and Disease 02.05.2018 Kandersteg, Switzerland Baumgartner Johanna;
Kardiovaskuläres Kolloquium des Schweizer Herz- und Gefässzentrums Bern Individual talk Linking macrophages, fats and inflammation - immune mechanisms in atherosclerosis 17.08.2017 University of Bern, Switzerland Freigang Stefan;
Cardiovascular and Metabolic Research Meeting 2016 Talk given at a conference Immune recognition of lipids in inflammation 15.01.2016 Fribourg, Switzerland Freigang Stefan;
Microbes and metabolites: implications for cardiovascular and metabolic health and disease (CVM Mini-Symposium) Talk given at a conference Fatty acids as pro- and anti-inflammatory mediators in metabolic disease 03.12.2015 Lausanne, Switzerland Freigang Stefan;
Research Seminar Series, Department of Pathology and Immunology, University of Geneva Individual talk Innate immune recognition of lipids in vascular inflammation 27.11.2015 Geneva, Switzerland Freigang Stefan;
Annual meeting of the Swiss Society of Cardiology 2015 Talk given at a conference A novel pathway of inflammation in atherosclerosis 12.06.2015 Zurich, Switzerland Freigang Stefan;
Endocrinology/Diabetes - Seminar series, University of Basel Individual talk Fatty acids in the induction and resolution of inflammation 01.04.2015 Basel, Switzerland Freigang Stefan;
World Immune Regulation Meeting WIRM-IX Talk given at a conference Immune Regulation by Oxidized Phospholipids 18.03.2015 Davos, Switzerland Freigang Stefan;
Seminar series, Zurich Center for Integrative Human Physiology (ZIHP) Individual talk Mitochondrial control of vascular inflammation 24.02.2015 Zurich, Switzerland Freigang Stefan;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Meeting of the Swiss Heart Foundation Talk 21.04.2015 Zurich, Switzerland Freigang Stefan;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media A patent for oxidised fat ETH life German-speaking Switzerland International 2016
Media relations: print media, online media Arteriosclerosi: malattia sociale. Scoperto un nuovo fattore scatenante. ATS / AgenziaTelegrafica Svizzera Italian-speaking Switzerland Western Switzerland 2015
Media relations: print media, online media BETRIFFT Forschung: Neue Studie weckt Hoffnung Schweizer Illustrierte German-speaking Switzerland 2015
Media relations: print media, online media Der Volkskrankheit Arteriosklerose auf der Spur fricktal24.ch German-speaking Switzerland 2015
Media relations: print media, online media Herausragende Wissenschaftler für medizinische Forschung prämiert Medienmitteilung Stiftung Pfizer Forschungspreis German-speaking Switzerland Italian-speaking Switzerland Western Switzerland 2015
Media relations: print media, online media Herzstiftung Schweiz OTX World German-speaking Switzerland 2015
Media relations: print media, online media Herzstiftung verleiht Preis an Arteriosklerose-Forscher Schweizerische Depeschenagentur sda German-speaking Switzerland 2015
Media relations: print media, online media Herzstiftung: Volkskrankheit Arteriosklerose: Neuer Auslöser entdeckt twitter.com Italian-speaking Switzerland German-speaking Switzerland Western Switzerland International 2015
Media relations: print media, online media Médecin zurichois primé Le Temps Western Switzerland 2015
Media relations: print media, online media Spark Award 2015 Finalists: Cyclic lipids as therapeutic agents for acute and chronic inflammation Youtube / ETH Zurich International 2015
Media relations: print media, online media Volkskrankheit Arteriosklerose Schweizerische Ärztezeitung German-speaking Switzerland Western Switzerland 2015
Media relations: print media, online media Volkskrankheit Arteriosklerose: Neuer Auslöser entdeckt Medienmitteilung Schweizerische Herzstiftung Western Switzerland German-speaking Switzerland Italian-speaking Switzerland 2015

Awards

Title Year
UniBE International 2021 (PhD student fellowship) 2017
Pfizer Research Prize 2015 2015
Research Prize of the Swiss Heart Foundation 2015

Associated projects

Number Title Start Funding scheme
157702 An apparatus for the real-time analysis of cellular metabolism 01.12.2014 R'EQUIP

Abstract

Cardiovascular diseases, in particular atherosclerosis, remain the leading cause of death worldwide; they also induce substantial morbidity and health care costs. Although dietary and pharmacological interventions are currently used to manage major risk factors, there is no effective treatment available that directly targets vascular inflammation. Metabolic dysfunction and chronic inflammation reciprocally interact in the pathogenesis of metabolic diseases, including atherosclerosis. Still, our understanding of the molecular mechanisms underlying this metabolic-immunological crosstalk remains very limited. We have recently characterized a novel pathway that selectively induces IL-1a-driven vascular inflammation and atherogenesis in response to metabolic perturbation. Our study identified fatty acid-induced respiratory uncoupling as the metabolic signal that triggers IL-1a secretion but simultaneously inhibits inflammasome activation and IL-1ß responses. These findings defined mitochondrial uncoupling as a previously unknown regulatory mechanism that relays metabolic stress to chronic inflammation. We therefore intent to investigate the role of physiological uncoupling in the regulation of IL-1 responses in atherosclerosis, metabolic dysfunction and microbial infection. We anticipate that these studies will not only extend our current understanding of a novel basic mechanism that links chronic inflammation and metabolic dysfunction, but will also identify new molecular targets that could be evaluated for the treatment of auto-inflammatory syndromes and metabolic disorders, such as obesity, diabetes and cardiovascular disease.
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