Kupffer cell–like syncytia replenish resident macrophage function in the fibrotic liver

Author:

Peiseler Moritz1234ORCID,Araujo David Bruna12ORCID,Zindel Joel125ORCID,Surewaard Bas G. J.12ORCID,Lee Woo-Yong12ORCID,Heymann Felix3ORCID,Nusse Ysbrand12ORCID,Castanheira Fernanda V. S.12,Shim Raymond12ORCID,Guillot Adrien3ORCID,Bruneau Alix3ORCID,Atif Jawairia6ORCID,Perciani Catia6ORCID,Ohland Christina12ORCID,Ganguli Mukherjee Priyanka7,Niehrs Annika8ORCID,Thuenauer Roland8ORCID,Altfeld Marcus8,Amrein Mathias7,Liu Zhaoyuan9ORCID,Gordon Paul M. K.10ORCID,McCoy Kathy1211ORCID,Deniset Justin121213ORCID,MacParland Sonya6ORCID,Ginhoux Florent1415ORCID,Tacke Frank3ORCID,Kubes Paul12ORCID

Affiliation:

1. Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.

2. Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

3. Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany.

4. Berlin Institute of Health (BIH), Berlin, Germany.

5. Department of Visceral Surgery and Medicine, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.

6. Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.

7. Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada.

8. Leibniz Institute of Virology (LIV), Hamburg, Germany.

9. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

10. Centre for Health Genomics and Informatics, University of Calgary, Calgary, Alberta, Canada.

11. Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

12. Department of Cardiac Sciences, University of Calgary, Calgary, Alberta, Canada.

13. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

14. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

15. Gustave Roussy Cancer Campus, INSERM U1015, Villejuif, France.

Abstract

Kupffer cells (KCs) are localized in liver sinusoids but extend pseudopods to parenchymal cells to maintain their identity and serve as the body’s central bacterial filter. Liver cirrhosis drastically alters vascular architecture, but how KCs adapt is unclear. We used a mouse model of liver fibrosis and human tissue to examine immune adaptation. Fibrosis forced KCs to lose contact with parenchymal cells, down-regulating “KC identity,” which rendered them incapable of clearing bacteria. Commensals stimulated the recruitment of monocytes through CD44 to a spatially distinct vascular compartment. There, recruited monocytes formed large aggregates of multinucleated cells (syncytia) that expressed phenotypical KC markers and displayed enhanced bacterial capture ability. Syncytia formed via CD36 and were observed in human cirrhosis as a possible antimicrobial defense that evolved with fibrosis.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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