The Important Roles of Natural Killer Cells in Liver Fibrosis
Abstract
1. Introduction
2. The Phenotypes of NK Cells in the Liver
3. The Profibrotic Function of NK Cells
4. The Anti-Fibrotic Function of NK Cells
5. Cellular and Molecular Factors Interfere with the Interaction of NK Cells with HSCs
5.1. CD96
5.2. CTLA-4
5.3. EP3
5.4. KIR
5.5. KLRG1
5.6. Metabotropic Glutamate Receptor 5
5.7. NKG2D Ligands or Stimulators
5.8. PD-1
5.9. Siglecs
5.10. STATs
5.11. TIGIT
Molecules | Function | References |
---|---|---|
CD96 | CD96, an exhaustion marker for NK cells, can be induced by TGF-β1. Blockade of the interaction of CD96 and its ligand CD155 can restore the function of NK cells. | [57] |
CTLA-4 | CTLA-4 expressed by Tregs can suppress NK cell activation by releasing cytokines such as IL-8 and TGF-β1 to suppress the expression of NKG2D ligand MHC class I chain-related proteins A and B (MIC-A/B) and HLA class I on HSCs. | [62] |
EP3 | Specific depletion of E-prostanoid 3 receptor (EP3) in NK cells can aggregate carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis. The cytotoxicity of CD27+CD11b+NK cells against activated HSCs is suppressed by EP3 deletion. | [45] |
KIR | Adoptive transfer of splenocytes enriched with NK cells that have undergone inhibitory killer-cell immunoglobulin-like receptor (iKIR) knockdown by small interfering RNAs (siRNAs) can reduce CCl4-induced liver fibrosis in BALB/c male SCID-Beige mice (lacking B/T/NK cells), evidenced by reduced expression of collagen and α-SMA. | [64] |
KLRG1 | The frequency of killer cell lectin-like receptor subfamily G member 1 (KLRG1)-expressing NK cells displayed anti-fibrotic effects in patients with chronic hepatitis B (CHB). | [65] |
mGluR5 | Mice with NK cell-specific knockout metabotropic glutamate receptor 5 (mGluR5) have aggravated CCl4-induced liver fibrosis compared to wild-type mice. In contrast, activation of mGluR5 can increase NK cell cytotoxicity against activated HSCs by upregulating the expression of anti-fibrotic genes, such as PRF1 (perforin), KLRK1 (killer cell lectin-like receptor K1), and IFN-γ production. | [67] |
NKG2D | Treatments such as poly(I:C) or IFN-γ can stimulate the expression of NKG2D on NK cells to increase its cytotoxicity against activated HSCs. | [70] |
PD-1 | The expression of exhaustion marker PD-1 in NK cells was positively associated with advanced liver fibrosis and NK cell dysfunction. | [76] |
Siglec-7 | The frequency of peripheral blood Siglec-7+CD56dimNK cells was decreased in patients with NAFLD with different stages of liver fibrosis, whereas the frequency of dysfunctional Siglec-7−PD-1+CD57+CD56dimNK cells was increased. | [11] |
STAT1 | STAT1 deletion in human NK cell line NK-92 cells can inhibit cell proliferation, promote cell apoptosis, and impair cell cytotoxicity. | [27] |
STAT3 | Treatment of dihydromyricetin (DHM) can inhibit HSC activation in vitro and decrease CCl4-induced liver fibrosis in C57BL/6 mice by improving NK cell killing ability and IFN-γ expression through the NF-κB/STAT3 pathway. | [82] |
TIGIT | TIGIT deficiency can inhibit parasite (Schistosoma japonicum) infection-induced liver fibrosis by increasing NK cell-mediated apoptosis HSCs. | [83] |
6. Treatments Improve the Cytolytic Function of NK Cells to HSCs
6.1. ADH Inhibitor
6.2. MicroRNAs
6.3. NKG2D Stimulators
6.4. NLRP3 Inflammasome Regulation
6.5. Ras Homology Family Member A (RhoA) Kinase Inhibitor
6.6. γδT Cells
6.7. Tim-3
7. Liver Resident NK Cells
8. Clinical Evaluations
Treatment | Function | References |
---|---|---|
Rosuvastatin (RSV) | RSV administration can significantly increase CD3+ CD16+ CD56+ NKT cells and reduce the percentage of Tim-3+NK cells in patients with CHB compared to the controls. | [104] |
TLR-8 agonist GS-9688 | In vitro treatment with GS-9688 can induce the expression of interferon-γ and TNF-α in NK cells to enhance their cytolytic function against hepatocytes. In addition, GS-9688 can increase the frequency of activated NK cells in patients with HBV. | [114] |
TLR 7 agonist GS-9620 | Administration of GS-9620 increased NK cell activation and function but did not decrease the levels of HBsAg in patients with suppression of HBV infection by nucleos(t)ide analogue (NA) therapy. | [115] |
A combination of pegylated interferon-alpha (peg-IFN-α) and NA therapy | The combined treatment can effectively reduce HBsAg by increasing the frequency and absolute number of circulating CD56brightNK cells, compared with the NA treatment group, whereas the CD56dimNK cells were decreased. | [116] |
Peg-IFN-α and sequential NA treatment | CHB patients receiving Peg-IFN-α and sequential NA treatment showed a decrease in HBsAg due to an increase in a subset of distinct NK cells, expressing NK cell activation receptors NKp30 and NKp46 with increased IFN-γ production and cytotoxicity. | [117] |
Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil | The frequency and the absolute number of NKp30+NK cells were significantly increased, which was accompanied by increased expression of CD107a and IFN-γ in patients with CHB during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil. | [118] |
Sorafenib | Sorafenib treatment can reduce the percentage of CD56brightCD16−NK cells and increase the frequency of CD56dimCD16+NK cells and the expression of granzyme B and perforin in total NK cells and both subsets of cells, improving the overall survival in HCC patients. | [119] |
RG-101, an N-acetylgalactosamine-conjugated anti-microRNA-122 oligonucleotide | A single subcutaneous administration of RG-101 (2 mg/kg) increased the frequency of NK cells in PBMCs and decreased plasma HCV RNA and IFN-γ-induced protein 10 (IP-10) levels in patients. | [120] |
IFN or IL-2 and therapeutic vaccine with IFN | Combination therapy with IFN and other immunomodulators such as IL-2 can enhance HBeAg in patients with entecavir treatment by significantly increasing peripheral CD56brightCD16−NK cells and decreasing regulatory T cells. | [121] |
Arthrospira | Treatment with Arthrospira, a genus of free-floating filamentous cyanobacteria, increased serum IFN-γ levels but decreased serum TNF-α and IL-6 and hepatic fibrosis and steatosis in CHB patients receiving NA therapy. | [122] |
9. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Yang, M.; Vanderwert, E.; Kimchi, E.T.; Staveley-O’Carroll, K.F.; Li, G. The Important Roles of Natural Killer Cells in Liver Fibrosis. Biomedicines 2023, 11, 1391. https://doi.org/10.3390/biomedicines11051391
Yang M, Vanderwert E, Kimchi ET, Staveley-O’Carroll KF, Li G. The Important Roles of Natural Killer Cells in Liver Fibrosis. Biomedicines. 2023; 11(5):1391. https://doi.org/10.3390/biomedicines11051391
Chicago/Turabian StyleYang, Ming, Ethan Vanderwert, Eric T. Kimchi, Kevin F. Staveley-O’Carroll, and Guangfu Li. 2023. "The Important Roles of Natural Killer Cells in Liver Fibrosis" Biomedicines 11, no. 5: 1391. https://doi.org/10.3390/biomedicines11051391
APA StyleYang, M., Vanderwert, E., Kimchi, E. T., Staveley-O’Carroll, K. F., & Li, G. (2023). The Important Roles of Natural Killer Cells in Liver Fibrosis. Biomedicines, 11(5), 1391. https://doi.org/10.3390/biomedicines11051391