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

Aleksandra Deczkowska,Eran Elinav,Dominik Pfister,Ido Yofe,Pierluigi Ramadori,David Goitein,Shing Kam,Yousuf Suhail,Yana Davidov,Chamutal Gur,Mengjie Qiu,Hila Hermon,Shir Shlomi-Loubaton,Amir Giladi,Sandrine Henri,Bernard Malissen,Assaf Weiner,Oren Barboy,Achim Weber,Mariya Likhter,Eylon Lahat,Eyal David,Susanne Roth,Mathias Heikenwälder,Gil Ben Yakov,Diego Adhemar Jaitin,Michal Cohen ,Ziv Ben‐Ari ,Oranit Cohen‐Ezra ,Michael Safran

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.

Highlights

As gene expression analysis of hepatic conventional dendritic cells (cDCs) in non-alcoholic steatohepatitis (NASH) livers revealed signatures related to increased migration and antigen presentation and T cell activation was previously implicated in NASH worsening in mice and humans[9,10,12,13,30], we investigated molecular signatures of DC–T cell pairs in liver-draining lymph nodes in the methionine and choline-deficient diet (MCDD)
XCR1+ cDC1 cells in a genetic mouse model and partial depletion of cDC1 from the liver using an XCL1-blocking antibody in two different paradigms of NASH induction, we observed that cDC1 cells promote liver inflammation and injury in NASH
Analysis of DC–T cell interacting partners in liver-draining lymph nodes revealed that excessive cDCs may potentiate pro-inflammatory CD8+ T cells, previously linked to NASH exacerbation

Summary

Results

ScRNA-seq of liver immune populations along NASH progression. To identify key immune players in NASH development and progression, we first used the model of methionine and choline-deficient diet (MCDD) feeding in mice, a model that faithfully recapitulates key features of human progression to NASH, including macrovesicular steatosis, ballooning, Mallory–Denk body formation, hepatocyte death and prominent immune infiltration (Extended Data Fig. 1a)[20,21]. As gene expression analysis of hepatic cDCs in NASH livers revealed signatures related to increased migration and antigen presentation and T cell activation was previously implicated in NASH worsening in mice and humans[9,10,12,13,30], we investigated molecular signatures of DC–T cell pairs in liver-draining lymph nodes in the MCDD model of NASH. Liver lymph-node-resident cDC1 cells and, to a lesser extent, cDC2 cells, showed more inflammatory interaction-induced gene expression in the MCDD condition compared to ND (Extended Data Fig. 7d,e).

Discussion

Methods

Code availability