The Important Roles of Natural Killer Cells in Liver Fibrosis

Abstract

Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP₃) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis.

Keywords: cellular and molecular mechanisms; hepatic stellate cells; liver fibrosis; natural killer cells; treatments.

Figure 1

NK cell maturation and functional subsets. (A) Maturing NK cells can be divided into four populations by characterizing the expression of CD11b and CD27; these populations include CD11b⁻CD27⁻NK cells, CD11b⁻CD27⁺NK cells, CD11b⁺CD27⁺NK cells, and CD11b⁺CD27⁻NK cells. CD11b⁻CD27⁻NK cells are immature NK cells with differentiation potential, both CD11b⁻CD27⁺NK cells and CD11b⁺CD27⁺NK cells have the best ability to secrete cytokines, and CD11b⁺CD27⁻NK cells display high cytolytic function. (B) Human NK cells can also be classified into three functional subsets, tolerant NK cells (CD56^brightCD27⁻CD11b⁻), regulatory NK cells (CD56^brightCD27⁺CD11b^+/−), and cytotoxic NK cells (CD56^dimCD27⁻CD11b⁺).

Figure 2

Activation of EP₃ can improve the cytotoxicity of CD27⁺CD11b⁺ NK cells against activated hepatic stellate cells (HSCs). Mechanistically, activation of prostaglandin E receptor 3 (EP₃) can increase the nuclear translocation of phosphorylated Spi-C transcription factor (Spic) by regulating protein kinase C (PKC) to upregulate integrin alpha-4 (Itga4, or CD49d) in NK cells. The binding of NK cells with activated HSCs is mediated by the interaction of Itga4 with vascular cell adhesion molecule 1 (VCAM1).

Figure 3

Comparison of mouse and human liver resident NK cells and conventional NK cells. The transcription factors in lr-NK cells and cNK cells are different, and they also express different surface markers and effector molecules. Abbreviations: cNK: conventional NK cell; Eomes: eomesodermin; FasL: Fas ligand; GM-CSF: granulocyte-macrophage colony-stimulating factor; lr-NK: liver resident NK; NKG2A: killer cell lectin-like receptor C1; T-bet: T-box transcription factor; TRAIL: TNF-related apoptosis-inducing ligand.