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; Sandrine Henri; Yousuf Suhail; Mengjie Qiu; Shing Kam; Hila Hermon; Eylon Lahat; Gil Ben Yakov; Oranit 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

doi:10.1038/s41591-021-01344-3

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, Sandrine Henri, Yousuf Suhail, Mengjie Qiu, Shing Kam, Hila Hermon, Eylon Lahat, Gil Ben Yakov, Oranit Cohen-EzraYana Davidov, Mariya Likhter, David Goitein, Susanne Roth, Achim Weber, Bernard Malissen, Assaf Weiner, Ziv Ben-Ari, Mathias Heikenwälder, Eran Elinav, Ido Amit

Weizmann Institute of Science, Tel Aviv University

Research output: Contribution to journal › Article › peer-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 XCR1 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 language	English
Pages (from-to)	1043-1054
Number of pages	12
Journal	Nature Medicine
Volume	27
Issue number	6
Early online date	20 May 2021
DOIs	https://doi.org/10.1038/s41591-021-01344-3
State	Published - 1 Jun 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1038/s41591-021-01344-3

Cite this

Deczkowska, A., David, E., Ramadori, P., Pfister, D., Safran, M., At The, B., Giladi, A., Jaitin, D. A., Barboy, O., Cohen, M., Yofe, I., Gur, C., Henri, S., Suhail, Y., Qiu, M., Kam, S., Hermon, H., Lahat, E., Ben Yakov, G., ... Amit, I. (2021). XCR1⁺ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nature Medicine, 27(6), 1043-1054. https://doi.org/10.1038/s41591-021-01344-3

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title = "XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis",

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 XCR1 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.",

author = "Aleksandra Deczkowska and Eyal David and Pierluigi Ramadori and Dominik Pfister and Michael Safran and \{At The\}, Baoguo and Amir Giladi and Jaitin, \{Diego Adhemar\} and Oren Barboy and Merav Cohen and Ido Yofe and Chamutal Gur and Sandrine Henri and Yousuf Suhail and Mengjie Qiu and Shing Kam and Hila Hermon and Eylon Lahat and \{Ben Yakov\}, Gil and Oranit Cohen-Ezra and Yana Davidov and Mariya Likhter and David Goitein and Susanne Roth and Achim Weber and Bernard Malissen and Assaf Weiner and Ziv Ben-Ari and Mathias Heikenw{\"a}lder and Eran Elinav and Ido Amit",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

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doi = "10.1038/s41591-021-01344-3",

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Deczkowska, A, David, E, Ramadori, P, Pfister, D, Safran, M, At The, B, Giladi, A, Jaitin, DA, Barboy, O, Cohen, M, Yofe, I, Gur, C, Henri, S, Suhail, Y, Qiu, M, Kam, S, Hermon, H, Lahat, E, Ben Yakov, G, Cohen-Ezra, O, Davidov, Y, Likhter, M, Goitein, D, Roth, S, Weber, A, Malissen, B, Weiner, A, Ben-Ari, Z, Heikenwälder, M, Elinav, E & Amit, I 2021, 'XCR1⁺ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis', Nature Medicine, vol. 27, no. 6, pp. 1043-1054. https://doi.org/10.1038/s41591-021-01344-3

TY - JOUR

T1 - XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis

AU - Deczkowska, Aleksandra

AU - David, Eyal

AU - Ramadori, Pierluigi

AU - Pfister, Dominik

AU - Safran, Michael

AU - At The, Baoguo

AU - Giladi, Amir

AU - Jaitin, Diego Adhemar

AU - Barboy, Oren

AU - Cohen, Merav

AU - Yofe, Ido

AU - Gur, Chamutal

AU - Henri, Sandrine

AU - Suhail, Yousuf

AU - Qiu, Mengjie

AU - Kam, Shing

AU - Hermon, Hila

AU - Lahat, Eylon

AU - Ben Yakov, Gil

AU - Cohen-Ezra, Oranit

AU - Davidov, Yana

AU - Likhter, Mariya

AU - Goitein, David

AU - Roth, Susanne

AU - Weber, Achim

AU - Malissen, Bernard

AU - Weiner, Assaf

AU - Ben-Ari, Ziv

AU - Heikenwälder, Mathias

AU - Elinav, Eran

AU - Amit, Ido

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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 XCR1 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.

AB - 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 XCR1 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.

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U2 - 10.1038/s41591-021-01344-3

DO - 10.1038/s41591-021-01344-3

M3 - مقالة

C2 - 34017133

SN - 1078-8956

VL - 27

SP - 1043

EP - 1054

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -