XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis

Aleksandra Deczkowska*, Eyal David, Pierluigi Ramadori, Dominik Pfister, Michael Safran, Baoguo At the, Amir Giladi, Diego Adhemar Jaitin, Oren Barboy, Merav Cohen, Ido Yofe, Chamutal Gur, Shir Shlomi-Loubaton, Sandrine Henri, Yousuf Suhail, Mengjie Qiu, Shing Kam, Hila Hermon, Eylon Lahat, Gil Ben YakovOranit Cohen-Ezra, Yana Davidov, Mariya Likhter, David Goitein, Susanne Roth, Achim Weber, Bernard Malissen, Assaf Weiner, Ziv Ben-Ari, Mathias Heikenwälder, Eran Elinav, Ido Amit

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.

Original languageEnglish
Pages (from-to)1043-1054
Number of pages12
JournalNature Medicine
Volume27
Issue number6
DOIs
StatePublished - Jun 2021

Funding

FundersFunder number
DKFZ-MOST
Daniel Morris Trust
Deutsch-Israelische Projektkooperation
Dr. Ludwik Wallach Cancer Research Fund
European Crohn’s and Colitis Organization
German-Israeli Cooperation in Cancer Research
Helen and Martin Kimmel award for innovative investigation
Helmholtz Future
Horizon 2020, Research Foundation Flanders30826052
IDSA Foundation
IPMP
ISF Israel Precision Medicine Program
Jeanne and Joseph Nissim Center for Life Sciences Research
NeuroMac DFG/TransregionalPA-1604 08459
Park Avenue Charitable Fund
Pearl Welinsky Merlo Scientific Progress Research Fund
Swiss Society Institute for Cancer Prevention Research
Wolfson Foundation and Family Charitable Trust
Howard Hughes Medical Institute724471-HemTree2.0
Bill and Melinda Gates Foundation
European Molecular Biology Organization7395
Melanoma Research Alliance509044, 703/15
Leona M. and Harry B. Helmsley Charitable Trust
Canadian Institute for Advanced Research
Merck KGaA
Wellcome Trust
Horizon 2020 Framework Programme683000
H2020 European Research Council
Thompson Family Foundation
European Research CouncilSFBTR179, SFBTR1335, SFBTR 209
Wolfson Foundation
Helmholtz-GemeinschaftZT-0027
Else Kröner-Fresenius-Stiftung
Fonds Wetenschappelijk Onderzoek
Garvan Institute of Medical Research
Israel Science Foundation
Deutsche Krebshilfe70113166, 70113167
Ministry of Science and Technology, Israel
Ministry of Health, State of Israel
Wolfson Family Charitable Trust
Helmholtz Association

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