The Impact of Liver Failure on the Immune System
Abstract
:1. Introduction
2. Role of the Liver in Immune Response
3. Immunometabolism and Mitochondrial Dysfunction in ACLF
4. The Gut–Liver Axis and Initiation of Hepatic Inflammation
5. Systemic Inflammation
6. Mediators of Inflammation
6.1. Cytokines
6.1.1. Cytokines as Prognostic Biomarkers
6.1.2. Cytokines as Potential Therapeutic Targets
6.2. Chemokines
6.3. Growth Factors
6.4. Lipid Mediators
7. Immunosuppression
7.1. Innate Immune Response
7.1.1. Neutrophils
Neutrophils | |||
---|---|---|---|
Author (Year) | Article Type | Number of patients | Conclusions |
Mookerjee R. P. et al. (2007) [86] | Research Article | 63 patients with alcoholic cirrhosis and cirrhosis superimposed on AH | Full activation of neutrophils resulting from the presence of humoral factors such as endotoxin is associated with reversible impairment of their immune response to infection |
Fiuza C. et al. (2002) [87] | Research Article | 14 patients with liver cirrhosis and 14 healthy controls | Increased neutrophil adhesion to microvascular endothelium and deficient transendothelial migration in patients with liver cirrhosis. G-CSF increases neutrophil transendothelial migration in patients with cirrhosis |
Kedarisetty C. K. et al. (2015) [88] | Randomized Controlled Trial | 55 patients with decompensated liver cirrhosis | Reduced mortality and reduced symptom severity during 12 months of follow-up in patients treated with G-CSF and darbepoetin α |
Konstantis G. et al. (2023) [90] | Systematic Review and Meta-Analysis of Randomized Controlled Trials | 421 patients with ACLF | Reduced mortality and improved MELD scores in patients treated with G-CSF. There is no correlation between improved Child–Pugh score or complication rates. |
Hou X. et al. (2021) [91] | Systematic Review and Meta-Analysis of Randomized Controlled Trials | 479 patients with ACLF | Overall, there is no association between G-CSF treatment and reduced risk of death or complications. Correlation with better survival in the Asian population. |
7.1.2. Macrophages
7.1.3. Natural Killer Cells (NK Cells)
Natural Killer Cells (NK Cells) | |||
---|---|---|---|
Author (Year) | Article Type | Number of Patients | Conclusions |
Weiss E. et al. (2021) [99] | Research Article | 67 patients with decompensated cirrhosis (including 35 critically ill patients with ACLF in the intensive care unit) and 12 healthy subjects | Increased numbers of neutrophils and macrophage M0-like monocytes and decreased numbers of several lymphocyte subsets (including memory lymphocytes) in patients with ACLF |
Radaeva S. et al. (2006) [101] | Research Article | Not applicable (mouse model) | NK cells killed activated hepatic stellate cells (HSCs), alleviating liver fibrosis. This process depended on retinoic acid early inducible 1/NKG2D and tumor necrosis factor-related apoptosis-inducing ligand. |
Jeong W. Il et al. (2011) [100] | Research Article | Not applicable (mouse model) | Transforming growth factor-β (TGF-β), produced by indirectly activated HSCs, reduced NK cell cytotoxicity, including that targeting HSCs. It has been suggested that retinol/SOCS1/TGF-b metabolites may be therapeutic targets and improve treatment efficacy with IFN-c and NK cell therapy. |
Li H. J. et al. (2022) [102] | Research Article | 37 HBV-ACLF patients and 13 control subjects | Reduced number of NK cells in the blood of ACLF patients and altered phenotypic and functional profile of NK. The observed association of these disorders with excessive CXCL-10 production |
Macrophages | |||
---|---|---|---|
Author (Year) | Article Type | Number of Patients | Conclusions |
Bernsmeier C. et al. (2015) [95] | Research article | 41 patients with ACLF, 9 patients with acute decompensation of cirrhosis without ACLF, 17 patients with cirrhosis without decompensation, 23 patients with acute liver failure, 29 healthy individuals | Patients with ACLF have higher numbers of immunoregulatory monocytes and macrophages expressing MERTK, suppressing the innate immune response to microbes. MERTK inhibitors can restore the production of inflammatory cytokines by immune cells from ACLF patients and may be developed to enhance the innate immune response in these individuals |
Kou K. et al. (2022) [96] | Review article | Not applicable (number of patients not mentioned) | Monocytes and macrophages show decreased HLA-DR expression and increased MERTK expression. |
Li Z.-H. et al. (2023) [97] | Research article | Not applicable (mouse model) | In ACLF mice, MSCs enhanced liver function and 48-h survival while reducing inflammatory injury by promoting M2 macrophage polarization and increasing Mertk expression levels in macrophages. |
7.2. Adaptive Immune Response
7.2.1. B Cells
7.2.2. T Cells
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ACLF | Acute, chronic liver failure |
ALD | Alcoholic liver disease |
APCs | Antigen-presenting cells |
bFGF | Basic fibroblast growth factor |
CAID | Cirrhosis-associated immune dysfunction |
CCL5 | C-C motif chemokine ligand 5 |
CLIF-C | Chronic Liver Failure Consortium |
COX | Cyclooxygenase |
DAMPs | Danger-associated molecular patterns |
EP2 | Prostaglandin E receptor 2 |
FGF21 | Fibroblast growth factor 21 |
FoxO | Forkhead box O |
G-CSF | Granulocyte colony-stimulating factor |
GM-CSF | Granulocyte-macrophage colony-stimulating factor |
GPCRs | G-protein-coupled receptors |
HBV-ACLF | Hepatitis B virus-related acute-on-chronic liver failure |
HMG1 | High mobility protein group 1 |
IFN-γ | Interferon-gamma |
iNKT | Invariant killer T cells |
KC | Kupffer cells |
LTE4 | Leukotriene E 4 |
LSEC | Liver sinusoidal endothelial cells |
MELD | Model of End-Stage Liver Disease |
MERTK | Mer receptor tyrosine kinase |
NAFLD | Non-alcoholic fatty liver disease |
NK | Natural killer |
NLRs | NOD-like receptors |
PAMPs | Pathogen-associated molecular patterns |
PG | Prostaglandin |
PGE2 | Derived eicosanoid prostaglandin E2 |
PHLF | Post-hepatectomy liver failure |
PRRs | Pattern recognition receptors |
SCF | Stem cell factor |
TLRs | Toll-like receptors |
TIPS | Transjugular intrahepatic portal-systemic shunt |
TGF-β1/IL-31 | Transforming growth factor β1/interleukin-31 |
12-HHT | 12-Hydroxyheptadecatrienoic acid |
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Impaired Function of Immune System | Treatment Possibilities | Treatment Effects |
---|---|---|
Activation of IFN-Î3/STAT1 anti-regenerative pathway | F-652 (IL-22 Fc) | Reduction in Lille and MELD scores, decrease in serum cytokine and chemokine levels. |
Increased levels of IL-11 | Anti IL-11 antibodies | Reduced fibrosis, anti-inflammatory effect, reduced hepatocyte death |
Increased levels of PGE2 | Human albumin solution | Improved macrophage function, Reduced infection risk |
Impaired neutrophil phagocytosis, chemotaxis, superoxide production, and attenuated degranulation | G-CSF | Improvement in Child–Pugh and MELD scores reduced short-term mortality |
Immune Cells | Effector Molecules | Action |
---|---|---|
Plasma and Memory B cells | IgA, IgG, IgE | Eliminate antigen |
Th1 | IFNγ, TNF, IL-2, Lymphotoxin | Pro-inflammatory |
Th2 | IL-4, IL-5, IL-6, IL-10, IL-13 | Pro-inflammatory, Allergy |
Th9 | IL-9, IL-10, IL-21 | Pro-inflammatory |
Th17 | IL-17, IL-21, IL-22, IL-25, IL-26 | Pro-inflammatory |
Th22 | IL-22 | Pro-inflammatory |
Treg | TGFβ, IL-10, IL-35 | Anti-inflammatory |
Tfh | IFNγ, STAT3, IL-4, IL-10, IL-21 | Help B cell activation |
CTL | Perforin, Granzyme, INFγ, TNFα, TNFβ | Tumor cell/ Lyse infected |
MC | TNFα, IL-1β, IL-6, IL-12, IL-23, MCP1, ROS | Pro-inflammatory |
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Dąbrowska, A.; Wilczyński, B.; Mastalerz, J.; Kucharczyk, J.; Kulbacka, J.; Szewczyk, A.; Rembiałkowska, N. The Impact of Liver Failure on the Immune System. Int. J. Mol. Sci. 2024, 25, 9522. https://doi.org/10.3390/ijms25179522
Dąbrowska A, Wilczyński B, Mastalerz J, Kucharczyk J, Kulbacka J, Szewczyk A, Rembiałkowska N. The Impact of Liver Failure on the Immune System. International Journal of Molecular Sciences. 2024; 25(17):9522. https://doi.org/10.3390/ijms25179522
Chicago/Turabian StyleDąbrowska, Alicja, Bartosz Wilczyński, Jakub Mastalerz, Julia Kucharczyk, Julita Kulbacka, Anna Szewczyk, and Nina Rembiałkowska. 2024. "The Impact of Liver Failure on the Immune System" International Journal of Molecular Sciences 25, no. 17: 9522. https://doi.org/10.3390/ijms25179522