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

, Eyal David, Pierluigi Ramadori, Dominik Pfister, Michael Safran, Baoguo At The, Amir Giladi, Diego Adhemar Jaitin, Oren Barboy, Merav Cohen,
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Published: 20 May 2021
Nature Medicine , Volume 27, pp 1043-1054; doi:10.1038/s41591-021-01344-3

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. Single-cell analyses reveal cDC1 as conserved immunological drivers of non-alcoholic steatohepatitis in mice and humans
Keywords: Chronic inflammation / Dendritic cells / Metabolic syndrome / Biomedicine / general / Cancer Research / Metabolic Diseases / Infectious Diseases / Molecular Medicine / Neurosciences

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