Role of NOD2 and S100A8/S100A9 in the pathogenesis of Coxsackievirus B3-induced myocarditis
| dc.contributor.advisor | Tschöpe, Carsten | |
| dc.contributor.advisor | Linthout, Sophie Van | |
| dc.contributor.author | Müller, Irene | |
| dc.contributor.grantor | Technische Universität Berlin | en |
| dc.contributor.referee | Kurreck, Jens | |
| dc.contributor.referee | Lauster, Roland | |
| dc.contributor.referee | Tschöpe, Carsten | |
| dc.contributor.referee | Linthout, Sophie Van | |
| dc.date.accepted | 2016-12-14 | |
| dc.date.accessioned | 2017-06-02T15:04:48Z | |
| dc.date.available | 2017-06-02T15:04:48Z | |
| dc.date.issued | 2017 | |
| dc.description.abstract | Cardiac inflammation plays a crucial role in Coxsackievirus B3 (CVB3)-induced myocarditis and is a consequence of viral-related cardiomyocyte injury, which activates the innate immune system. The nucleotide binding oligomerization domain 2 (NOD2), a cytoplasmatic pattern-recognition receptor (PRR), is responsible for the recognition of single stranded (ss) RNA. The alarmins S100A8 and S100A9 are damage-associated molecular patterns (DAMPs) and have been shown to be of importance in several cardiovascular disorders. NOD2 and the alarmins belong to the innate immune system. Furthermore, the NLR family, pyrin domain containing 3 (NLRP3) inflammasome plays an important role in CVB3 myocarditis, whereby a relationship between NOD2 and NLRP3 has been described. S100A8/S100A9 acts as an inducer of reactive oxygen species (ROS) production, which is an NLRP3 activator. Overall, the role of NOD2, S100A8 and S100A9 in CVB3-induced myocarditis has not been explored so far. Briefly, our group demonstrated recently that NOD2 knockdown (-/-) mice are protected from deleterious CVB3-induced effects versus WT CVB3 mice. The aim of our first study was to further investigate the role of NOD2 and its connection to NLRP3 in CVB3-induced myocarditis models. In a second study, we wanted to examine the importance of S100A8 and S100A9 and their connection to NLRP3 in the same experimental models as for NOD2. In the first study, we demonstrated that NOD2 is up-regulated in CVB3-positive patients compared to acute myocarditis (AMC), dilated cardiomyopathy and control patients. In vitro, we further confirmed the relevance of NOD2 in experimental CVB3-mediated myocarditis and determined its link to the NLRP3 inflammasome, as shown by the patients, in vivo, and in vitro data. In the scope of a second study, we demonstrated that S100A8 and S100A9 are elevated in endomyocardial biopsies of CVB3-positive patients compared to control patients. The S100A9-/- animal study demonstrated the detrimental role of S100A8 and S100A9 in CVB3-induced myocarditis, as shown by reduced cardiac chemokine production, less cardiac immune cell infiltrates, suppression of cardiac oxidative stress and RAGE signaling, lower Coxsackievirus and adenovirus receptor levels and CVB3 copy number, and an improved LV function in S100A9-/- CVB3-infected mice versus WT CVB3 animals. Exogenous application of S100A8 to S100A9-/- CVB3 mice induced a severe myocarditis similar to WT CVB3 mice. In in vitro experiments, we confirmed the deteriorating effect of both alarmins. Furthermore, our in vivo and in vitro results demonstrated a link between alarmins and the NLRP3 inflammasome system. The decreased RAGE and Dia-1 expression in CVB3-infected S100A9-/- mice compared to respective CVB3 controls, which in case of RAGE was also confirmed in vitro, may be an indicator for S100A8- and S100A9-signaling via RAGE and Dia-1 in CVB3-induced myocarditis. These data predict a model where in CVB3-induced myocarditis, NOD2 is responsible for CVB3 sensing and NLRP3 activation, and is probably therefore the main source of the inflammatory disorder. In parallel, the CVB3 infection results in an elevation of S100A8 and S100A9, which induces a signaling cascade via RAGE and Dia-1, resulting in an increased inflammatory cell migration and oxidative stress, particularly ROS. The latter is considered to lead to myocardial injury in AMC patients and to exacerbate inflammation. High ROS production in myocarditis in turn boosts the inflammatory disorder. In this vicious circle, ROS activates the NLRP3 inflammasome and in turn boosts the inflammatory disorder. Prevailing pharmacological treatment of myocarditis-associated cardiomyopathy targets mainly the neuroendocrine system but does not directly influence the virus-induced inflammation and oxidative stress. Since NOD2 and NLRP3 are involved in the inflammatory disorder and S100A8 and S100A9 seem to play a role in oxidative stress, these molecules may represent new potential pharmaceutical targets for the treatment of (CVB3-induced) myocarditis. | en |
| dc.description.abstract | In der ersten Studie konnten wir zeigen, dass NOD2 in CVB3 positiven Patienten im Vergleich zu Patienten mit akuter Myokarditis (AMC), dilatativer Kardiomyopathie und Kontrollprobanden hochreguliert ist. In vitro haben wir weiterhin die Relevanz von NOD2 in der experimentellen CVB3 induzierten Kardiomyopatie bestätigt und konnten den Link zum NLRP3 Inflammasom nachweisen, wie an Hand der Patienten-, in vivo- und in vitro-Daten gezeigt wurde. Im Rahmen einer zweiten Studie konnten wir nachweisen, dass S100A8 und S100A9 in Endomyokardbiopsien von CVB3 positiven Patienten im Vergleich zu Kontrollpatienten erhöht sind. Die S100A9-/- Tierstudie zeigte eine schädigende Rolle von S100A8 und S100A9 in der CVB3 induzierten Myokarditis, wie demonstriert an Hand von reduzierter kardialer Chemokinprodukation, weniger kardialer Zellinfiltrate, einem geringeren oxidativen Stress und RAGE Signaling, verminderte Levels des Coxsackievirus und Adenovirus Rezeptors und CVB3 Kopienzahlen und eine verbesserte kardiale linksventrikuläre Funktion in S100A9-/- CVB3 infizierten Mäusen versus WT CVB3 Tieren. Eine exogene Gabe von S100A8 und S100A9 zu S100A9-/- CVB3 Mäusen, induzierte eine schwere Myokarditis, ähnllich wie in CVB3 Mäusen. In in vitro Experimenten konnten wir den negativen Effekt von beiden Alarminen bestätigen. Weiterhin zeigen unsere in vivo und in vitro Daten einen Link zwischen den Alarminen und dem NLRP3 Inflammasomsystem. Die reduzierte RAGE und Dia-1 Expression in CVB3 infizierten S100A9-/- Mäusen, welches im Falle von RAGE auch in vitro bestätigt wurde, kann ein Indikator für ein S100A8 and S100A9 Signaling via RAGE und Dia-1 in der CVB3 induzierten Myokarditis sein. An Hand dieser Daten kann ein Model postuliert werden, in dem in der CVB3 induzierten Myokarditis NOD2 für die CVB3 Erkennung und die NLRP3 Aktivierung zuständig ist und womöglich eine Hauptquelle für den inflammatorischen Stress ist. Gleichzeitig resultiert die CVB3 Infektion in einer S100A8 und S100A9 Erhöhung, welche die RAGE und Dia-1 Kaskade induziert, die zu einer Zunahme der Migration von inflammatorischen Zellen und des oxidativen Stresses führt, besonders ROS. Letzteres kann in AMC Patienten zur Myokardschädigung führen und verschlimmert die Entzündung. Eine hohe ROS Produktion in der Myokarditis fördert die Entzündungsreaktion. In diesem Teufelskreis aktiviert ROS das NLRP3 Inflammasom und kurbelt die Inflammation an. Bestehende pharmakologische Behandlungen bei Myokarditis assoziierten Kardiomyopathien setzen am neuroendonkrinen System an und beeinflussen jedoch nicht die CVB3 induzierte Inflammation oder den oxidativen Stress. Da NOD2 und NLRP3 in die Entzündungsreaktion involviert sind und S100A8 und S100A9 beim oxidativen Stress eine Rolle zu spielen scheinen, könnten diese Moleküle ein neues potentielles therapeutisches Target für die Behandlung von (CVB3 induzierten) Myokarditis darstellen. | de |
| dc.identifier.uri | https://depositonce.tu-berlin.de/handle/11303/6384 | |
| dc.identifier.uri | http://dx.doi.org/10.14279/depositonce-5934 | |
| dc.language.iso | en | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject.ddc | 572 Biochemie | de |
| dc.subject.other | Coxsackievirus B3-induced myocarditis | en |
| dc.subject.other | innate immunity | en |
| dc.subject.other | NOD2 | en |
| dc.subject.other | DAMPs | en |
| dc.subject.other | S100A8/S100A9 | en |
| dc.subject.other | Coxsackievirus B3 induzierte Myokarditis | de |
| dc.subject.other | angeborenes Immunsystem | de |
| dc.title | Role of NOD2 and S100A8/S100A9 in the pathogenesis of Coxsackievirus B3-induced myocarditis | en |
| dc.title.translated | Die Rolle von NOD2 und S100A8/S100A9 in der Pathogenese der Coxsackievirus B3 induzierten Myokarditis | de |
| dc.type | Doctoral Thesis | en |
| dc.type.version | acceptedVersion | en |
| tub.accessrights.dnb | free | en |
| tub.affiliation | Fak. 3 Prozesswissenschaften::Inst. Biotechnologie | de |
| tub.affiliation.faculty | Fak. 3 Prozesswissenschaften | de |
| tub.affiliation.institute | Inst. Biotechnologie | de |
| tub.publisher.universityorinstitution | Technische Universität Berlin | en |