XCR1+ type 1 conventional dendritic cells drive liver pathology in Non-Alcoholic Steatohepatitis [scRNA-seq]

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions, which 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 (cDC), 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 NALFD/NASH spectrum showed that cDC type 1 (cDC1) were more abundant and activated in disease. Genomic analysis of cDC-T pairs in 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. Indicated cell types were isolated by sorting from bone marrow/blood/liver/liver lymph nodes from mice kept on normal diet (ND) or methionine and choline deficient diet (MCDD) for two weeks (unless indicated otherwise). Please note that [1] the second read contained only cell and molecule barcodes. This information was appended to the fastq entry header. [2] *_metadata_s.txt file is meta data file associating each single cell with its amplification batch and index sorting readouts.