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

Nat Med. 2021 Jun;27(6):1043-1054. doi: 10.1038/s41591-021-01344-3. Epub 2021 May 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / pathology
  • Cellular Reprogramming / genetics
  • Cellular Reprogramming / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Fatty Liver / genetics
  • Fatty Liver / immunology*
  • Fatty Liver / pathology
  • Female
  • Humans
  • Liver / immunology
  • Liver / pathology
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Male
  • Mice
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / immunology*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, Chemokine / genetics*
  • Receptors, Chemokine / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology


  • Receptors, Chemokine
  • XC chemokine receptor 1, mouse