Journal
JOURNAL OF HEPATOLOGY
Volume 77, Issue 4, Pages 1136-1160Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2022.06.012
Keywords
NAFLD; NASH; Single-cell sequencing; spatial transcriptomics; Kupffer cells; immune-mediated liver disease; macrophages; cancer immunotherapy; HCC; exhausted T cells; PPAR agonists; FXR agonists; scRNA-seq; MAFLD
Categories
Funding
- BIH clinician scientist program
- German Research Foundation (DFG) [SFB/TRR 296, CRC1382, 403224013]
- German Ministry of Education and Research (BMBF DEEP-HCC consortium)
- NSERC [RGPIN/07191-2019]
- Heart & Stroke Foundation of Canada
- CIHR
- Canada Research Chairs Program
- European Reseach Council, EU (ERC) [272983813, SFB/TR 209, 314905040, 360372040, SFBTR179, SFBTR1335]
- Wilhelm Sander-Stiftung
- Research Foundation Flanders (FWO) [30826052]
- Rainer Hoenig Stiftung
- Deutsche Krebshilfe [70113166, 70113167]
- Horizon 2020 grant
- German-Israeli Cooperation in Cancer Research (DKFZ-MOST)
- ZukunftsthemaImmunology and Inflammation
- Helmholtz-Gemeinschaft
- NIH [CA190844, CA228483]
- German Ministry of Research and Education (BmBF) through the Liver Systems Medicine (LiSyM) network grant
- ERACOSysMed (Dynaflow) grant
- [ZT-0027]
Ask authors/readers for more resources
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and the immune system plays a significant role in different stages of NAFLD, with multiple inflammatory mechanisms involved. Recent research advancements have improved our understanding of the complex heterogeneity of liver immune cell subsets.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is emerging as the leading cause of cirrhosis, liver transplantation and hepatocellular carcinoma (HCC). NAFLD is a metabolic disease that is considered the hepatic manifestation of the metabolic syndrome; however, during the evolution of NAFLD from steatosis to non-alcoholic steatohepatitis (NASH), to more advanced stages of NASH with liver fibrosis, the immune system plays an integral role. Triggers for inflammation are rooted in hepatic (lipid overload, lipotoxicity, oxidative stress) and extrahepatic (gut-liver axis, adipose tissue, skeletal muscle) systems, resulting in unique immune-mediated pathomechanisms in NAFLD. In recent years, the implementation of single-cell RNA-sequencing and high dimensional multiomics (proteogenomics, lipidomics) and spatial transcriptomics have tremendously advanced our understanding of the complex heterogeneity of various liver immune cell subsets in health and disease. In NAFLD, several emerging inflammatory mechanisms have been uncovered, including profound macrophage heterogeneity, auto-aggressive T cells, the role of unconventional T cells and platelet-immune cell interactions, potentially yielding novel therapeutics. In this review, we will highlight the recent discoveries related to inflammation in NAFLD, discuss the role of immune cell subsets during the different stages of the disease (including disease regression) and integrate the multiple systems driving inflammation. We propose a refined concept by which the immune system contributes to all stages of NAFLD and discuss open scientific questions arising from this paradigm shift that need to be unravelled in the coming years. Finally, we discuss novel therapeutic approaches to target the multiple triggers of inflammation, including combination therapy via nuclear receptors (FXR agonists, PPAR agonists). (c) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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