The role of natural killer cells in liver inflammation - PubMed (original) (raw)

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The role of natural killer cells in liver inflammation

A J Highton et al. Semin Immunopathol. 2021 Aug.

Abstract

The liver is an important immunological site that can promote immune tolerance or activation. Natural killer (NK) cells are a major immune subset within the liver, and therefore understanding their role in liver homeostasis and inflammation is crucial. Due to their cytotoxic function, NK cells are important in the immune response against hepatotropic viral infections but are also involved in the inflammatory processes of autoimmune liver diseases and fatty liver disease. Whether NK cells primarily promote pro-inflammatory or tolerogenic responses is not known for many liver diseases. Understanding the involvement of NK cells in liver inflammation will be crucial in effective treatment and future immunotherapeutic targeting of NK cells in these disease settings. Here, we explore the role that NK cells play in inflammation of the liver in the context of viral infection, autoimmunity and fatty liver disease.

Keywords: Autoimmune liver disease; Fatty liver disease; Liver inflammation; NK cells; Viral hepatitis.

© 2021. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1

Fig. 1

Activating and inhibitory receptors expressed on NK cells. NK cell-activating receptors binding to their respective ligands promote activation and subsequent cytotoxicity and cytokine production, while inhibitory receptors oppose this response. Created with

BioRender.com

Fig. 2

Fig. 2

Subsets of NK cells present within the liver and vasculature. CD56bright cNK cells are located primarily within the vasculature. CD56dim cNK cells can be found within the vasculature and also in the liver parenchyma. Resident within the liver are lrNK cells expressing CCR5, CXCR3, CXCR6, CD69, CD49a and CD56. Created with

BioRender.com

Fig. 3

Fig. 3

Distinct phenotypes characterise mouse liver cNK cells and ILC1s at steady state. Liver leukocytes from naïve BALB/c mice were prepared for flow cytometric analysis. A Single live CD45+ cells were gated for CD3- TCRβ- CD19- NKp46+ cells, and B unsupervised nonlinear dimensional reduction using t-distributed stochastic neighbourhood embedding (tSNE) analysis was performed. Distinct clustering of cNK cells (blue population) and ILC1s (pink population) is shown. C Total NKp46+ cells analysed for CD49a and CD49b expression to distinguish ILC1s and cNK cells. D Histogram overlays for the indicated marker expression in ILC1s and cNK cells are shown. Data are concatenated from 3 mice and are representative of 3 independent experiments

Fig. 4

Fig. 4

Potential role of NK cells in promoting and reducing liver inflammation. NK cells can promote liver inflammation through the secretion of pro-inflammatory cytokines and the killing of hepatocytes and cholangiocytes. On the other hand, NK cells can reduce liver inflammation through the killing of activated T cells and other liver-resident cells. Created with

BioRender.com

Fig. 5

Fig. 5

NK cell targeted therapies. A virally infected cell A inhibiting an NK cell via signalling through NKG2A or B being killed due to blockade of inhibition with anti-NKG2A monoclonal antibody. C A CAR NK cell recognising an overexpressed surface protein on an infected cell via an engineered CAR receptor causing activation and subsequent killing. Created with

BioRender.com

References

    1. Freitas-Lopes M, Mafra K, David B, Carvalho-Gontijo R, Menezes G. Differential location and distribution of hepatic immune cells. Cells. 2017;6:48. doi: 10.3390/cells6040048. - DOI - PMC - PubMed
    1. Tanimine N, Tanaka Y, Abe T, Piao J, Chayama K, Ohdan H. Functional behavior of NKp46-positive intrahepatic natural killer cells against hepatitis C virus reinfection after liver transplantation. Transplantation. 2016;100:355–364. doi: 10.1097/TP.0000000000001031. - DOI - PubMed
    1. Lam VC, Lanier LL. NK cells in host responses to viral infections. Curr Opin Immunol. 2017;44:43–51. doi: 10.1016/j.coi.2016.11.003. - DOI - PMC - PubMed
    1. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009;86:513–528. doi: 10.1189/JLB.0309135. - DOI - PMC - PubMed
    1. Liu P, Chen L, Zhang H. Natural killer cells in liver disease and hepatocellular carcinoma and the nk cell-based immunotherapy. J Immunol Res. 2018;2018:1–8. doi: 10.1155/2018/1206737. - DOI - PMC - PubMed

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