XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.
Aleksandra DeczkowskaEyal DavidPierluigi RamadoriDominik PfisterMichael SafranBaoguo At TheAmir GiladiDiego Adhemar JaitinOren BarboyMerav CohenIdo YofeChamutal GurShir Shlomi-LoubatonSandrine HenriYousuf SuhailMengjie QiuShing KamHila HermonEylon LahatGil Ben YakovOranit Cohen-EzraYana DavidovMariya LikhterDavid GoiteinSusanne RothAchim WeberBernard MalissenAssaf WeinerZiv Ben-AriMathias F HeikenwälderEran ElinavBjørt K KragesteenPublished in: Nature medicine (2021)
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.
Keyphrases
- dendritic cells
- bone marrow
- cell cycle
- lymph node
- oxidative stress
- immune response
- liver failure
- chronic kidney disease
- type diabetes
- end stage renal disease
- mesenchymal stem cells
- ejection fraction
- gene expression
- cell proliferation
- high throughput
- insulin resistance
- prognostic factors
- metabolic syndrome
- rna seq
- peritoneal dialysis
- high fat diet induced