Die Rolle der Interleukin-15/Makrophagen Axia für die Immunantwort bei einer Leberfibrose

• Antragsteller: Professor Dr. Jan G. Hengstler, seit 6/2018
• Fachliche Zuordnung: Gastroenterologie ; Immunologie
• Förderung: Förderung von 2017 bis 2021
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 329715688

• Erstellungsjahr: 2021

Zusammenfassung der Projektergebnisse

Chronic liver diseases are of emerging importance in our society with a yearly increasing prevalence. To understand the molecular mechanisms behind the disease progression is crucial in order to prevent their progression. Our preliminary studies identified interleukin-15 (IL-15) as a pro-fibrotic cytokine, possibly promoting liver fibrosis in chronic liver injury. Based on our results, the main cellular source of IL-15 in the liver is Kupffer cells, a liver-specific type of macrophages. Although characterizing the specific role of IL-15 as a single cytokine in chronic liver disease was challenging, the findings led to the identification of a critical role of macrophages, one of the main sources of IL-15. In chronic liver disease infiltrating macrophages form crown-like structures formation in non-alcoholic fatty liver disease. This macrophage infiltration contributes to a bile transport impairment in affected hepatocytes, namely vesicular regurgitation of bile from bile canaliculi into hepatocytes. Macrophage depletion efficiently blocked this vesicular regurgitation and can offer an important target in future drug development against the progression of NAFLD. We faced an important challenge in the project after a year of the project period as the identification of IL-15 expression in fibrotic liver and the IL-15 deletion in floxed IL-15 mice turned out to be difficult. However, the role of macrophages as main source of IL-15 could nevertheless be clarified and led to the major finding of vesicular regurgitation of bile in NAFLD.

Projektbezogene Publikationen (Auswahl)

• Pipe-3D: a pipeline based on immunofluorescence, 3D confocal imaging, reconstructions, and morphometry for biliary network analysis in cholestasis. In: Experimental cholestasis research (S. 25-53) / edited by Mathieu Vinken. New York: Springer, 2019. (Methods in molecular biology, 1981)
  Damle-Vartak, A.; Begher-Tibbe, B.; Gunther, G.; Geisler, F.; Vartak, N.; Hengstler, J. G.
  
• Enhanced activation of human NK cells by drug-exposed hepatocytes. Arch. Toxicol. 94: 439–448 (2020)
  Fasbender, F.; Obholzer, M.; Metzler, S.; Stöber, R.; Hengstler, J. G.; Watzl, C.
  
• Hepatotoxic pyrrolizidine alkaloids induce DNA damage response in rat liver in a 28-day feeding study. Arch. Toxicol. 94: 1739-1751 (2020)
  Ebmeyer, J.; Rasinger, J. D.; Hengstler, J. G.; Schaudien, D.; Creutzenberg, O.; Lampen, A.; Braeuning, A.; Hessel-Pras, S.
  
• Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease. Arch. Toxicol. 94: 205-217 (2020)
  Campos, G.; Ghallab, A.; Pütter, L.; Edlund, K.; Cadenas, C.; Marchan, R.; Hengstler, J. G.; Godoy, P.
  
• Intravital dynamic and correlative imaging reveals diffusiondominated canalicular and flow-augmented ductular bile flux. Hepatology 2020 Jun 19
  Vartak, N.; Guenther, G.; Joly, F.; Damle-Vartak, A.; Begher-Tibbe, B.; Ghallab, A.; Drasdo, D.; Hengstler, J. G.
  
• Towards improved hepatocyte cultures: Progress and limitatios. Food Chem. Toxicol. 138: article no. 111188 (2020)
  Ruoß, M.; Vosough, M.; Königsrainer, A.; Nadalin, S.; Wagner, S.; Sajadian, S.; Hengstler, J. G.; Nussler, A. K.