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

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Title: XCR1+type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis
Authors: Deczkowska, Aleksandra, David, Eyal, Ramadori, Pierluigi, Pfister, Dominik, Safran, Michael, At the, Baoguo, Giladi, Amir, Jaitin, Diego Adhemar, Barboy, Oren, Cohen, Merav, Yofe, Ido, Gur, Chamutal, Shlomi-Loubaton, Shir, Henri, Sandrine, Suhail, Yousuf, Qiu, Mengjie, Kam, Shing, Hermon, Hila, Lahat, Eylon, Ben Yakov, Gil, Cohen-Ezra, Oranit, Davidov, Yana, Likhter, Mariya, Goitein, David, Roth, Susanne, Weber, Achim, Malissen, Bernard, Weiner, Assaf, Ben-Ari, Ziv, Heikenwälder, Mathias, Elinav, Eran, Amit, Ido
Source: Nature Medicine; 20210101, Issue: Preprints p1-12, 12p
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 XCR1DTAmice 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.
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  Data: Nature Medicine; 20210101, Issue: Preprints p1-12, 12p
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  Data: 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 XCR1DTAmice 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.
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