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

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

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