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XCR1 + type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.
- Source :
-
Nature medicine [Nat Med] 2021 Jun; Vol. 27 (6), pp. 1043-1054. Date of Electronic Publication: 2021 May 20. - Publication Year :
- 2021
-
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 <superscript>DTA</superscript> 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 <superscript>+</superscript> cDC1 as an important driver of liver pathology.
- Subjects :
- Animals
Bone Marrow Cells immunology
Bone Marrow Cells pathology
Cellular Reprogramming genetics
Cellular Reprogramming immunology
Dendritic Cells pathology
Diet, High-Fat adverse effects
Disease Models, Animal
Fatty Liver genetics
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 pathology
Receptors, Chemokine immunology
T-Lymphocytes immunology
T-Lymphocytes pathology
Dendritic Cells immunology
Fatty Liver immunology
Non-alcoholic Fatty Liver Disease immunology
Receptors, Chemokine genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 27
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 34017133
- Full Text :
- https://doi.org/10.1038/s41591-021-01344-3