Publikationsserver der Universitätsbibliothek Marburg
Titel:Die immunregulativen Funktionen von adenosine deaminase acting on RNA 1 (ADAR1)
Autor:Großmann, Jenny
Weitere Beteiligte: Bauer, Stefan (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0182
URN: urn:nbn:de:hebis:04-z2014-01828
DOI: https://doi.org/10.17192/z2014.0182
DDC: Medizin
Titel (trans.):The immunoregulatory functions of adenosine deaminase acting on RNA 1 (ADAR1)
Publikationsdatum:2014-02-19
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
TRIF, IRF3, Typ I Interferon, dendritische Zellen, Type I Interferon, TRIF, Makrophagen, differentiation, IRF3, ADAR1, ADAR1, Differenzierung, Editierung

Zusammenfassung:
Im Rahmen dieser Arbeit wurden die immunregulativen Funktionen von ADAR1 charakterisiert. Die besondere Domänenstruktur sowie die IFN-Induzierbarkeit von ADAR1 lassen eine Funktion über die Editierung bekannter, neuronal spezifischer Substrate hinaus annehmen. Durch einige Studien wurde diesbezüglich ein Zusammenhang von ADAR1 mit Typ I IFN-Signalwegen diskutiert, aber die Substrate bzw. die zugrundeliegenden Mechanismen sind weitgehend unverstanden. Daher sollte die ADAR1-abhängige Beteiligung an der Typ I IFN-Antwort, im Kontext verschiedener PRR-Liganden und Viren, in verschiedenen Immunzellen ADAR1-defizienter Modelle untersucht und mögliche zelltypspezifische Effekte charakterisiert werden. Für die Untersuchungen wurden murine ADAR1-defiziente Makrophagen und dendritische Zellen auf Grundlage des Cre/loxP-Rekombinationssystems generiert (ADAR1f7-9/LysMCre oder CD11cCre). Für das humane System wurde ein siRNA-vermittelter Knockdown in Monozyten etabliert. Die Untersuchung des Typ I IFN-Aktivierungspotentials von ADAR1-defizienten im Vergleich zu ADAR1-kompetenten, murinen Makrophagen sowie von humanen Monozyten durch verschiedene PRR-Liganden und Viren zeigte eine stark ADAR1-abhängige, modulierte Sekretion von Typ I IFN (Abb. 6.1). Während die Stimulation mit TRIF-abhängigen PRR-Liganden zu einer verstärkten IFNβ-Freisetzung führte, war die Typ I IFN-Antwort nach Stimulation mit viralen PAMPs oder Infektion mit Viren, die die Signalgebung TRIF-unabhängig vermitteln, in ADAR1-defizienten Zellen stark reduziert. Weitere Untersuchungen der für die Typ I IFN-Signalgebung wichtigen Moleküle offenbarten eine ausgeprägte Typ I IFN-Signatur in ADAR1-defizienten Zellen nach TRIF-abhängiger Stimulation entsprechend den beobachteten erhöhten IFNβ-Spiegeln. Überraschenderweise wurde auch im Kontext TRIF-unabhängiger Stimulation die Typ I IFN-Signatur durch die ADAR1-Defizienz erhöht, während aber die Typ I IFN-Freisetzung stark reduziert war. Besonders die Expression von IRF3 sowie der aktivierten, phosphorylierten Form war sowohl nach TRIF-abhängiger als auch nach TRIF-unabhängiger Stimulation erhöht. Immunfluoreszenz-Daten zeigten, dass im Kontext TRIF-unabhängiger Stimulation trotz der erhöhten IRF3-Expression, die nukleäre Translokation in ADAR1-defizienten Makrophagen ausblieb, während die TRIF-abhängige Stimulation eine effiziente IRF3-Translokation vermittelte. Diese Daten weisen ADAR1 eine bisher unbekannte Funktion als wichtigen Modulator der IRF3-vermittelten Typ I IFN-Antwort zu. In diesem Zusammenhang übt ADAR1 zum einen eine inhibitorische Funktion auf die TRIF-IRF3-Achse der Typ I IFN-Induktion aus. Zum anderen wird die IRF3-Translokation über die TRIF-unabhängige Signalgebung durch ADAR1 begünstigt, womit sich ADAR1 hier als Aktivator der IRF3-vermittelten Typ I IFN-Antwort zeigt. Folgerichtig konnte kein signifikanter, ADAR1-abhängiger Effekt auf das Typ I IFN-Aktivierungspotential von pDCs beobachtet werden, die als auf IFN-Produktion spezialisierte Zellen die Typ I IFN-Antwort unabhängig von IRF3 induzieren. Zukünftige Untersuchungen werden die zugrundeliegenden Mechanismen der modulatorischen Funktionen von ADAR1 auf die IRF3-Translokation sowie auf die TRIF-Aktivität klären müssen. Im Zuge der Untersuchung verschiedener ADAR1-defizienter Immunzellen wurde über den modulatorischen Effekt auf die Typ I IFN-Antwort hinaus, eine kritische Rolle der ADAR1-Funktion auf die Differenzierung von bestimmten cDCs in vitro sowie in vivo aufgezeigt. In vitro blieb in ADAR1-defizienten GM-CSF-Kulturen die Differenzierung zu mDCs vollständig aus, während in vivo die CD103-positive cDC-Zellpopulation in verschiedenen peripheren Organen konditionell ADAR1-defizienter Mäuse nicht detektiert werden konnte. Da sowohl die in vitro generierten mDCs als auch die CD103-positiven cDC-Population in vivo in Abhängigkeit von der GM-CSF-Signalgebung stehen, liegt ein durch die ADAR1-Defizienz-vermittelter Defekt dieser Signalgebung nahe. Weiterführende Experimente werden dies sowie einen möglichen Zusammenhang der dysregulierten cDC-Differenzierung mit den in Makrophagen beobachteten erhöhten Typ I IFN-Signatur klären müssen.

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