Dysfunktionale Kupffer-Zellen führen zu unkontrollierten Infektionen bei Leberzirrhose

• Antragsteller: Dr. Moritz Peiseler
• Fachliche Zuordnung: Gastroenterologie ; Immunologie
• Förderung: Förderung von 2017 bis 2021
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 386680738

• Erstellungsjahr: 2021

Zusammenfassung der Projektergebnisse

The liver is an important immune organ and serves as the body’s central filter of blood, preventing blood stream infections. Kupffer cells (KCs) are the main cellular component of the hepatic filter, ideally located in the liver sinusoids and equipped with an array of specialized receptors allowing the capture of a wide range of microbes under sheer conditions from the blood stream. Depletion of KCs leads to rapid mortality of the host. Liver cirrhosis is the common end-stage of many chronic liver diseases including alcoholic liver disease, nonalcoholic fatty liver disease and chronic viral hepatitis. Despite the different aetiologies leading to cirrhosis, the fibrotic remodeling and architectural changes are similar, including profound changes to the liver vasculature, such as capillarization of sinusoids, development of intrahepatic shunts and formation of collaterals vessels. The liver filter has been optimized to function in unperturbed sinusoids, and it is unclear how fibrotic changes in the liver vasculature affect KC function. While patients with liver cirrhosis suffer from an increased risk of fatal infections, millions of people worldwide suffer from chronic liver diseases without increases in blood stream infections, suggesting some capacity of the fibrotic liver to adapt. We sought to investigate how the KC compartment deals with the changes during liver fibrosis. Using intravital microscopy, which offers the unique possibility to study immune processes in real time in living organisms, we systematically assessed KC function in mice with experimental liver fibrosis induced by repetitive administration of carbon tetrachloride (CCl4). With this imaging approach, we were able to study liver hemodynamics and anatomical changes to the liver vasculature and noticed many features resembling human cirrhosis such as altered blood flow and formation of high flow collateral vessels. KCs, which require intimate cell-cell contacts with parenchymal cells to maintain their identity, changed their morphology, downregulated KC identity molecules and seemed to be detached from their KC niche. Functionally, this led to a profound impairment of KCs in the liver sinusoids to capture and eradicate intravenously injected S. aureus. Surprisingly however, when subjected to a survival study after S. aureus infection, the difference in survival between healthy and fibrotic mice was minimal. When assessing the macrophage compartment on a larger scale, we noticed aggregates of giant macrophages in liver venules, that were extraordinarily efficient at capturing and eradicating injected S. aureus, thus compensating for impaired KCs in the liver sinusoids. Phenotypical characterization revealed that these giant cells expressed typical KC markers and linage tracing and parabiosis experiments demonstrated a bone marrow origin, showing these were in fact bone marrow-derived giant Kupffer cells. Mechanistically, CD44 and its ligand hyaluronan mediated the recruitment of macrophages to form giant KCs and the scavenger receptor CD36 mediated their tight fusion to giant cells. Importantly, the presence of intravascular giant KCs conformed a survival benefit in experimental sepsis. Lastly, we found that the cues directing the recruitment and phenotype of giant KCs were at least partially provided by intestinal microbiota, as germ-free and dysbiotic mice lacked giant KCs. We identified a hitherto unknown role for intravascular giant cell formation, namely the recruitment of bone marrow-derived monocytes to form giant KCs, maintaining the liver firewall in fibrosis, a potentially lifesaving adaptation and important consideration before implementing monocyte-targeting therapies.

Projektbezogene Publikationen (Auswahl)

• More friend than foe: The emerging role of neutrophils in tissue repair, J. Clin. Invest. 129 (2019) 2629–2639
  M. Peiseler, P. Kubes
  
• Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination, J. Clin. Invest. 129 (2019) 4643–4656
  S.K. Jorch, B.G.J. Surewaard, M. Hossain, M. Peiseler, C. Deppermann, J. Deng, A. Bogoslowski, F. van der Wal, A. Omri, M.J. Hickey, P. Kubes
  
• Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer, Nat. Med. 25 (2019) 641–655
  M. Malehmir, D. Pfister, S. Gallage, M. Szydlowska, D. Inverso, E. Kotsiliti, V. Leone, M. Peiseler, B.G.J. Surewaard, D. Rath, A. Ali, M.J. Wolf, H. Drescher, M.E. Healy, D. Dauch, D. Kroy, O. Krenkel, M. Kohlhepp, (…) , F. Tacke, R. Rad, M. Matter, N. Djouder, P. Kubes, P.A. Knolle, K. Unger, L. Zender, B. Nieswandt, M. Gawaz, A. Weber, M. Heikenwalder
  
• Patrolling Alveolar Macrophages Conceal Bacteria from the Immune System to Maintain Homeostasis., Cell. (2020)
  A.S. Neupane, M. Willson, A.K. Chojnacki, F. Vargas E Silva Castanheira, C. Morehouse, A. Carestia, A.E. Keller, M. Peiseler, A. DiGiandomenico, M.M. Kelly, M. Amrein, C. Jenne, A. Thanabalasuriar, P. Kubes
  
• Tacrolimus impairs Kupffer cell capacity to control bacteremia: why transplant recipients are susceptible to infection, Hepatology. (2020)
  C. Deppermann, M. Peiseler, J. Zindel, L. Zbytnuik, W. Lee, E. Pasini, C. Baciu, J. Matelski, Y. Lee, D. Kumar, A. Humar, B. Surewaard, P. Kubes, M. Bhat
  
• Primordial GATA6 macrophages function as extravascular platelets in sterile injury. Science. 371 (2021)
  J. Zindel, M. Peiseler, M. Hossain, C. Deppermann, W.Y. Lee, B. Haenni, B. Zuber, J.F. Deniset, B.G.J. Surewaard, D. Candinas, P. Kubes