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Gpnmb in Inflammatory and Metabolic Diseases

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Gpnmb in Inflammatory and Metabolic Diseases Functional characterization of Gpnmb in inflammatory and metabolic diseases Dissertation zur Erlangung des akademischen Grades D octor rerum naturalium (Dr. rer. nat.) eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin von M.Sc., Bernadette Nickl Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing. Dr. Sabine Kunst Dekan der Lebenswissenschaftlichen Fakultät Prof. Dr. Bernhard Grimm Gutachter: Prof. Dr. Michael Bader Prof. Dr. Karl Stangl Prof. Dr. Thomas Sommer Tag der mündlichen Prüfung: 28. Februar 2020 For Sayeeda Summary Summary In 2018, the World Health Organization reported for the first time that “Overweight and obesity are linked to more deaths worldwide than underweight”A. Obesity increases the risk for the development of diabetes, atherosclerosis and cardiovascular diseases. Those metabolic diseases are associated with inflammation and the expression of glycoprotein nonmetastatic melanoma protein b (Gpnmb), a transmembrane protein that is expressed by macrophages and dendritic cells. We studied the role of Gpnmb in genetically- and diet-induced atherosclerosis as well as diet-induced obesity in Gpnmb-knockout and respective wildtype control mice. To this purpose, a mouse deficient in Gpnmb was created using Crispr-Cas9 technology. Body weight and blood lipid parameters remained unaltered in both diseases. Gpnmb was strongly expressed in atherosclerotic lesion-associated macrophages. Nevertheless, the absence of Gpnmb did not affect the development of aortic lesion size. However, macrophage and inflammation markers in epididymal fat tissue were increased in Gpnmb-deficient mice. In comparison to atherosclerosis, the absence of Gpnmb elicited stronger effects in obesity. For the first time, we observed a positive influence of Gpnmb on insulin and glucose plasma levels. Obese Gpnmb-knockout mice displayed aggravated insulin resistance and liver fibrosis. The latter was associated with higher phosphorylated AKT levels and increased expression of lipogenic genes. Moreover, Gpnmb-knockout animals contained more macrophages in epididymal adipose tissue. Gpnmb was strongly expressed in adipose tissue macrophages in wildtype mice, suggesting an alleviating role of Gpnmb on adipose tissue inflammation. This is corroborated by in vitro data where Gpnmb was mostly expressed in reparative macrophages stimulated with transforming growth factor β (TGFβ). However, this expression resulted only in a mild anti-inflammatory effect. Another important macrophage feature, autophagy, was not influenced by Gpnmb. This is surprising as Gpnmb expression, shedding and degradation was uniquely increased by bafilomycin. This is an inhibitor of the last step of autophagy and lysosomal degradation. Bafilomycin moreover altered the glycosylation of Gpnmb, which was highly variable throughout the study. Either bafilomycin-mediated Gpnmb induction might result from lysosomal overload or from a side effect of bafilomycin that is promotion of cell differentiation. This is supported by the observation that Gpnmb expression responded strongest to differentiation into mature macrophages. Differentiation from day 6 to day 7 in vitro increased Gpnmb transcript levels 100-fold, whereas treatment with TGFβ doubled and with bafilomycin tripled Gpnmb transcript levels in the same time span. Taken together, Gpnmb expression is strongly induced in fully mature macrophages and can be further increased due to lysosomal inhibition. In obesity, the major risk factor for the development of diabetes type II, Gpnmb prevents the development of insulin resistance possibly by dampening adipose tissue inflammation. A https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight 3 4 Zusammenfassung Zusammenfassung Zum ersten Mal ist Übergewicht mit mehr Todesfällen weltweit verbunden als UntergewichtB. Übergewicht erhöht das Risiko für Diabetes, Arteriosklerose und Herz-Kreislauf-Erkrankungen. Diese gehen mit einer Entzündung und der Expression von Glykoprotein nonmetastatic melanoma protein b (Gpnmb) einher, einem Transmembranprotein, das hauptsächlich von Makrophagen und dendritschen Zellen exprimiert wird. Wir haben die Rolle von Gpnmb in genetisch- und ernährungsinduzierter Arteriosklerose sowie ernährungsinduzierter Adipositas bei Mäusen untersucht. Zu diesem Zweck wurden mit Hilfe der Crispr-Cas9-Technologie entsprechende Mauslinien ohne funktionales Gpnmb erzeugt. Gpnmb-Knockout-Tiere zeigten ähnliches Körpergewicht und ähnliche Blutfettwerte in beiden Erkrankungen wie ihre Wildtyp-Kontrolltiere. Wie erwartet besaßen Makrophagen in arteriosklerotischen Läsionen eine hohe Expression von Gpnmb. Trotzdem war das Ausmaß der Aortenläsion in arteriosklerotischen Gpnmb-Knockout-Tieren unverändert. Allerdings wurden im epididymalen Fettgewebe von Gpnmb-Knockout-Tieren mehr Makrophagenmarker exprimiert. In Adipositas wurden mehr Auffälligkeiten durch die Abwesenheit von Gpnmb detektiert. Wir konnten erstmals einen positiven Einfluss von Gpnmb auf den Insulin- und Glukoseplasmaspiegel zeigen. Adipöse Gpnmb-Knockout-Mäuse besaßen eine ausgeprägte Insulinresistenz und verstärkte Leberfibrose. Letzteres war mit einer erhöhten AKT Phosphorylierung und einer höheren Expression lipogener Genen assoziiert. Darüber hinaus enthielten die Gpnmb-Knockout-Tiere, wie bereits im vorherigen Arterioskleroseexperiment, mehr Makrophagen im epididymalen Fettgewebe. Diese zeigten in Wildtyp-Tieren eine starke Gpnmb-Expression, was auf eine lindernde Rolle von Gpnmb auf die Entzündung des Fettgewebes hindeutet. Dies wird durch in vitro-Daten bestätigt, wo Gpnmb am höchsten in Transforming growth factor β-(TGFβ)-stimulierten, reparativen Makrophagen exprimiert wurde. Allerdings war der entzündungshemmende Effekt von Gpnmb auf die Makrophagen gering. Zudem hatte Gpnmb keinen nachweisbaren Einfluss auf Autophagie, eine weitere wichtige Eigenschaft von Makrophagen. Das ist insofern überraschend, als dass wir eine Erhöhung der Gpnmb- Expression, seiner Abspaltung und seines Abbaus nach Stimulation mit Bafilomycin feststellen konnten. Dieser ist ein Inhibitor des letzten Schrittes der Autophagie und des lysosomalen Abbaus. Außerdem veränderte Bafilomycin die Glykosylierung von Gpnmb, welche durchgehend hochvariabel war. Somit wurde Gpnmb entweder durch lysosomalen Stress beeinflusst oder durch eine Nebenwirkung von Bafilomycin: der verstärkten Differenzierung von Zellen. Letzteres wird durch die Beobachtung bestätigt, dass die Expression von Gpnmb am stärksten auf die Differenzierung von Knochenmarkszellen hin zu reifen Makrophagen reagierte. Die Gpnmb-Trankriptlevel verdoppelten sich nach der Behandlung mit TGFβ innerhalb von 24 Stunden, verdreifachten sich mit Bafilomycin, aber verhundertfachten sich während der Differenzierung von Tag sechs zu Tag sieben in vitro. B https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight 5 Zusammenfassung Zusammengefasst wird die Gpnmb-Expression in vollentwickelten Makrophagen stark induziert und durch lysosomale Überlastung weiter erhöht. In Adipositas, einer der Hauptrisikofaktoren für Diabetes mellitus Typ II, kann es die Entwicklung einer Insulinresistenz verhindern, möglicherweise durch die Dämpfung der einhergehenden Entzündung im Fettgewebe. 6 Table of Contents Table of Contents SUMMARY ................................................................................................................................... 3 ZUSAMMENFASSUNG .................................................................................................................. 5 TABLE OF CONTENTS ................................................................................................................... 7 1. INTRODUCTION .................................................................................................................. 11 1.1. Metabolic syndrome ..........................................................................................................................11 1.1.1. Obesity ............................................................................................................................................. 12 1.1.2. Atherosclerosis ................................................................................................................................ 14 1.2. Structure and function of Gpnmb .......................................................................................................18 1.2.1. “Gpnmb” .......................................................................................................................................... 18 1.2.2. Structure of Gpnmb ......................................................................................................................... 19 1.2.3. Splicing ............................................................................................................................................. 20 1.2.4. Glycosylation ................................................................................................................................... 20 1.2.5. Mutations of Gpnmb ....................................................................................................................... 20 1.2.6. Interaction ....................................................................................................................................... 21 1.2.7. Shedding .......................................................................................................................................... 22 1.2.8.
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