The role of the sympathetic nervous system and semaphorins in the pathogenesis of endometriosis

Claudia Scheerer
2016 · doi:10.17169/refubium-10823 · W2272382602
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Endometriosis is characterized by sympathetic hypoinnervation and increased semaphorin expression, suggesting a neuroimmunomodulatory role in its pathogenesis and promoting chronic inflammation.

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This dissertation investigated whether chronic inflammatory sympathetic hypoinnervation occurs in peritoneal endometriosis and whether semaphorins (Sema 3C/3F) and the receptor Nrp2 are involved. Using tissue and peritoneal fluid analyses, the study confirmed reduced anti-inflammatory sympathetic nerve fibers not only in endometriosis-affected lesions but also in unaffected peritoneal tissue, found increased Sema 3C and Sema 3F expression in endometriotic tissue, and detected elevated Sema 3C and soluble Nrp2 in peritoneal fluid; relevant Sema receptors were present on sympathetic nerve fibers only in women with endometriosis, not controls. Serum expression showed no significant changes, and in vitro experiments indicated that endometriosis peritoneal fluid can repel sympathetic nerve fibers similarly to Semas, with only partial inhibition by Sema antibodies, implying additional repulsive factors and that effects are localized rather than systemic. The paper is centrally about endometriosis — specifically the sympathetic nervous system and semaphorin (Sema/Nrp2) pathways that may regulate peritoneal nerve fiber repulsion and neuro-immune modulation.

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Abstract

The widespread phenomenon of a sympathetic hypoinnervation during chronic inflammatory diseases, which was also shown in peritoneal endometriosis, could be verified in this study. The reduction of these anti-inflammatory nerve fibers during endometriosis, occurs in the endometriosis affected tissue, but also in the unaffected tissue of women with endometriosis, suggesting an overall impairment of the peritoneal cavity during peritoneal endometriosis. Our analysis revealed an over expression of Sema 3C and 3F in peritoneal endometriotic tissue. Further, in peritoneal fluid of endometriosis patients, an over expression of Sema 3C and the soluble form of its specific receptor, Nrp 2, was identified. The specific Sema receptors, which are known to be involved in the sympathetic nerve fiber repellence mechanisms, were identified on sympathetic nerve fibers only in peritoneal tissue of women with endometriosis and not without endometriosis. Analysis of Sema and receptors expression in serum of endometriosis patients revealed no significant results, suggesting that endometriosis is a disease of the peritoneal cavity and not systemic. Interestingly, Sema expression was identified in pivotal cells during inflammation, macrophages and activated fibroblasts. Therefore, Sema interactions during endometriosis are probably regulated by mechanisms of the immune response. Finally, suggesting a neuroimmunomodulation of nerve fibers during the pathogenesis of endometriosis. Furthermore, it could be shown that peritoneal fluid of women with endometriosis is insofar affected as it is able to cause sympathetic nerve fiber repulsion in vitro, similarly as Semas do, which was verified in this study. Effects of the endometriotic peritoneal fluid on sympathetic ganglia could only be partially inhibited by Semas antibodies, suggesting that further factors expressed in the peritoneal fluid of EM patients, are able to affect sympathetic axon growth. The expression of Semas and Nrp 2 in fibroblasts, could be regulated in vitro by treatment with endometriosis associated factors such as estrogen and TGF, but more importantly by the treatment with peritoneal fluid of endometriosis patients and not by treatment with peritoneal fluid of women without endometriosis. This result demonstrates clear differences in the properties of peritoneal fluid during endometriosis or unaffected by the disease. Furthermore, it demonstrates that the peritoneal fluid has a key role during the regulation of Sema expression during endometriosis. Altogether, this study demonstrates that a repulsion of sympathetic nerve fibers in the peritoneum of women with endometriosis might be regulated by neruoimmunomodulatory mechanisms involving the Sema pathway. Thereby, the anti-inflammatory acting sympathetic nervous system might be impaired and the chronic inflammatory state during endometriosis is promoted.
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Haupttitel: The role of the sympathetic nervous system and semaphorins in the pathogenesis of endometriosis Titel übersetzt: Die Rolle des sympathischen Nervensystems und Semaphorine in der Pathogenese der Endometriose Autor*in: Scheerer, Claudia Erscheinungsjahr: 2016 Datum der Freigabe: 2016-02-12T10:56:23.384Z Abstract: The widespread phenomenon of a sympathetic hypoinnervation during chronic inflammatory diseases, which was also shown in peritoneal endometriosis, could be verified in this study. The reduction of these anti-inflammatory nerve fibers during endometriosis, occurs in the endometriosis affected tissue, but also in the unaffected tissue of women with endometriosis, suggesting an overall impairment of the peritoneal cavity during peritoneal endometriosis. Our analysis revealed an over expression of Sema 3C and 3F in peritoneal endometriotic tissue. Further, in peritoneal fluid of endometriosis patients, an over expression of Sema 3C and the soluble form of its specific receptor, Nrp 2, was identified. The specific Sema receptors, which are known to be involved in the sympathetic nerve fiber repellence mechanisms, were identified on sympathetic nerve fibers only in peritoneal tissue of women with endometriosis and not without endometriosis. Analysis of Sema and receptors expression in serum of endometriosis patients revealed no significant results, suggesting that endometriosis is a disease of the peritoneal cavity and not systemic. Interestingly, Sema expression was identified in pivotal cells during inflammation, macrophages and activated fibroblasts. Therefore, Sema interactions during endometriosis are probably regulated by mechanisms of the immune response. Finally, suggesting a neuroimmunomodulation of nerve fibers during the pathogenesis of endometriosis. Furthermore, it could be shown that peritoneal fluid of women with endometriosis is insofar affected as it is able to cause sympathetic nerve fiber repulsion in vitro, similarly as Semas do, which was verified in this study. Effects of the endometriotic peritoneal fluid on sympathetic ganglia could only be partially inhibited by Semas antibodies, suggesting that further factors expressed in the peritoneal fluid of EM patients, are able to affect sympathetic axon growth. The expression of Semas and Nrp 2 in fibroblasts, could be regulated in vitro by treatment with endometriosis associated factors such as estrogen and TGF, but more importantly by the treatment with peritoneal fluid of endometriosis patients and not by treatment with peritoneal fluid of women without endometriosis. This result demonstrates clear differences in the properties of peritoneal fluid during endometriosis or unaffected by the disease. Furthermore, it demonstrates that the peritoneal fluid has a key role during the regulation of Sema expression during endometriosis. Altogether, this study demonstrates that a repulsion of sympathetic nerve fibers in the peritoneum of women with endometriosis might be regulated by neruoimmunomodulatory mechanisms involving the Sema pathway. Thereby, the anti-inflammatory acting sympathetic nervous system might be impaired and the chronic inflammatory state during endometriosis is promoted. Das weitverbreitete Phänomen einer sympathischen Hypoinnervation in chronisch- entzündlichen Erkrankungen, welches auch in der peritonealen Endometriose nachgewiesen wurde, konnte in dieser Studie bestätigt werden. Dabei zeigt sich nicht nur direkt in den Endometrioseläsionen eine verminderte Anzahl dieser anti-inflammatorischen Nervenfasern, sondern auch im nicht betroffenen Gewebe von Frauen mit Endometriose. Dieses Ergebnis deutet darauf hin, dass die gesamte Peritonealhöhle bei Patientinnen mit peritonealen Endometrioseläsionen betroffen ist. Unsere Analysen zeigten eine erhöhte Expression von Sema 3C und Sema 3F in peritonealem endometriotischem Gewebe. Zusätzlich konnte in der peritonealen Flüssigkeit eine erhöhte Expression von Sema 3C und dem zugehörigen Rezeptor Nrp 2 identifiziert werden. Besonders hervorzuheben ist, dass die spezifische Sema Rezeptoren, die eine wichtige Rolle im Prozess der Modulation sympathischer Nervenfasern spielen, nur auf Endometriose- assoziierten Nervenfasern exprimiert wurden. In Geweben von nicht Endometriosepatientinnen wurden sie hingegen nicht exprimiert. Die Expressionsanalysen von pro- und antiinflammatorischen Faktoren im Serum ergaben keine signifikanten Veränderungen, was darauf hindeutet, dass die Endometriose überwiegend zu lokalen inflammatorischen Veränderungen führt. Interessanterweise wurden Semas und Nrp 2 in inflammatorischen Zellen wie Makrophagen und aktivierten Fibroblasten gefunden. Daher liegt es nahe, dass die Sema Regulation durch Endometriose-assoziierte Immunprozesse beeinflusst wird und schlussendlich die Neuroimmunmodulation der Nervenfasern ein wichtiger Schlüsselfaktor in der Pathogenese der Endometriose darstellt. Die Peritonealflüssigkeit von Patientinnen mit Endometriose zeigt ähnliche Eigenschaften wie die Semas selbst und führt im in vitro Versuch zu einer Abstoßung/Schädigung sympathischer Nervenfasern. Die Effekte der endometriotischen Peritonealflüssigkeit auf sympathische Nervenfasern konnte teilweise durch Sema Antikörper inhibiert werden. Dies suggeriert, dass es weitere Nerven abstoßende Faktoren in der Peritonealflüssigkeit bei der Endometriose geben muss, welche diesen Prozess beeinflussen. Die Expression von Semas und Nrp 2 in Fibroblasten, konnte in in vitro Versuchen durch Endometriose-assoziierte Faktoren wie Östrogen und TGF reguliert werden. Wesentlich bedeutender war allerdings die Erkenntnis, dass die Peritonealflüssigkeit von erkrankten Frauen ebenfalls eine regulierende Wirkung zeigte, während die Peritonealflüssigkeit von gesunden Frauen keinen Effekt hatte. Dies zeigt deutlich die unterschiedlichen Eigenschaften der Peritonealflüssgkeiten von Frauen mit Endometriose und Gesunden. Außerdem, weisen diese Ergebnisse auf eine entscheidende Rolle der Peritonealflüssigkeit bei der Regulierung der Sema Expression während der Endometriose Erkrankung hin. Insgesamt zeigt die Studie, dass die Abstoßung von sympathischen Nervenfasern im Peritoneum von Frauen mit Endometriose durch neuroimmunmodulatorische Mechanismen des Sema Signalweges möglich wäre. Dementsprechend würde dies zu einer Reduktion der anti-inflammatorischen sympatischen Nervenfasern und somit den Weg für den chronischen Inflammationsprozess begünstigen. Weiterführende Untersuchungen könnten hier neue Wege der gezielten anti-inflammatorischen Therapie aufzeigen. Identifier: Sprache: Englisch Freie Schlagwörter: endometriosis semaphorins sympathetic nervous system semaphorins sympathetic nervous system DDC-Klassifikation: 570 Biowissenschaften; Biologie 619 Gynäkologie, Pädiatrie, Geriatrie 619 Gynäkologie, Pädiatrie, Geriatrie Publikationstyp: Dissertation Fachbereich/Einrichtung: Biologie, Chemie, Pharmazie Dissertation_Scheerer.pdf Beschreibung: PDF Größe: 3.872MB Format: PDF Prüfsumme (MD5): 087fa0f695a30f633d9d7dbe6a215894

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