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 - Shlomi-Loubaton, Shir
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
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/6
Y1 - 2021/6
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85106245484&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01344-3
DO - 10.1038/s41591-021-01344-3
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C2 - 34017133
AN - SCOPUS:85106245484
SN - 1078-8956
VL - 27
SP - 1043
EP - 1054
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -
