Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jun 9:13:867940.
doi: 10.3389/fendo.2022.867940. eCollection 2022.

Hepatic Stellate Cell-Immune Interactions in NASH

James K Carter  1   2 , Scott L Friedman  1
Affiliations
Review

Hepatic Stellate Cell-Immune Interactions in NASH

James K Carter et al. Front Endocrinol (Lausanne). .

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a more aggressive presentation of NAFLD, is characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation and heightened immune cell activity have emerged as hallmark features of NASH and key drivers of fibrosis through the activation of hepatic stellate cells (HSCs). Recent advances in our understanding of the molecular and cellular pathways in NASH have highlighted extensive crosstalk between HSCs and hepatic immune populations that strongly influences disease activity. Here, we review these findings, emphasizing the roles of HSCs in liver immunity and inflammation, key cell-cell interactions, and exciting areas for future investigation.

Keywords: NASH; fibrosis; hepatic stellate cells; immunity; inflammation.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
HSC-Immune Interactions in NASH Progression. Communication between hepatic stellate cells (HSCs) and immune cells amplify profibrogenic inflammatory signaling in NASH. HSCs respond to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) that are increased in NASH. Resident Kupffer cells (KCs) and recruited monocyte-derived macrophages (MoMFs) release cytokines that promote HSC activation and survival. Neutrophil myeloperoxidase (MPO) is directly activating to HSCs which secrete factors to prolong neutrophil survival. HSCs supply vitamin A to the sinusoidal niche where it is converted to retinoic acid (RA) by liver sinusoidal endothelial cells (LSECs) as an important signal to immune cells including α4β7 integrin positive gut homing CD4+ T cells. Lymphocytes, including B and CD8+ T cells, release HSC-activating cytokines like TNFα and IL-6. Natural killer T (NKT) cells promote HSC activation through release of osteopontin (Opn) and sonic hedgehog (Shh). Natural killer (NK) cells display reduced HSC killing due to increased insulin and TGFβ signaling.
Figure 2
Figure 2
HSC-Immune Interactions in NASH Regression. Key immune pathways oppose fibrogenesis during resolution of NASH injury. CD8+ memory and γδT cells induce apoptosis of activated HSCs. Neutrophil microRNA 223 (miR-223) converts pro-inflammatory macrophages to a restorative phenotype. Hepatocyte-released acetoacetate promotes anti-fibrogenic signaling by macrophages.
See this image and copyright information in PMC

References

    1. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. . Nonalcoholic Steatohepatitis is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States. Gastroenterology (2015) 148(3):547–55. doi: 10.1053/j.gastro.2014.11.039 - DOI - PubMed
    1. Younossi ZM. Non-Alcoholic Fatty Liver Disease - A Global Public Health Perspective. J Hepatol (2019) 70(3):531–44. doi: 10.1016/j.jhep.2018.10.033 - DOI - PubMed
    1. Loomba R, Friedman SL, Shulman GI. Mechanisms and Disease Consequences of Nonalcoholic Fatty Liver Disease. Cell (2021) 184(10):2537–64. doi: 10.1016/j.cell.2021.04.015 - DOI - PubMed
    1. Krenkel O, Tacke F. Liver Macrophages in Tissue Homeostasis and Disease. Nat Rev Immunol (2017) 17(5):306–21. doi: 10.1038/nri.2017.11 - DOI - PubMed
    1. Huby T, Gautier EL. Immune Cell-Mediated Features of non-Alcoholic Steatohepatitis. Nat Rev Immunol (2021) 5:1–15. doi: 10.1038/s41577-021-00639-3 - DOI - PMC - PubMed

Publication types

MeSH terms