Immune Checkpoints and the Immunology of Liver Fibrosis
Abstract
:1. Introduction
2. A Pathogenetic Overview of Liver Fibrosis
2.1. The Fibrotic Process
2.2. Cells Involved in Liver Fibrosis
2.2.1. Kupffer Cells and Liver Macrophages
2.2.2. Hepatic Stellate Cells
2.2.3. The Interplay Between KCs and HSCs
2.2.4. Liver Sinusoidal Endothelial Cells (LSECs)
2.2.5. Cytokines Involved in Liver Fibrosis
2.3. Resolution of Liver Fibrosis
3. Immunology of Liver Fibrosis
3.1. The Liver as an Immune Organ
3.2. Immune Factors Implicated in Liver Fibrosis
Innate and Adaptive Immunity
3.3. Innate Immunity in Liver Fibrosis
3.3.1. Cells Involved in Innate Immunity
3.3.2. LSECs as Gatekeepers of Innate and Adaptive Immunity
3.4. Adaptive Immunity T Cells
3.5. Unconventional T Cells
3.6. Extrahepatic Factors
3.7. The Interaction of Innate and Adaptive Immunity
4. Immune Checks in Liver Fibrosis
4.1. Immune Checkpoint
4.2. Association of Immune Checkpoints with Liver Fibrosis
4.2.1. The PD-1/PD-L1 Axis and CTLA-4
4.2.2. Other ICPs Involved in Liver Fibrosis
4.3. Therapeutic Implications of Checkpoint Inhibitors in Liver Fibrosis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Molecules | Functions | References |
---|---|---|
TGF-β | Primarily produced by macrophages. Enhances ECM production in HSCs through Smad-dependent pathways and Smad-independent pathways. | [131,132] |
PDGF | Produced by macrophages. It contributes to fibrosis progression through HSC activation. | [133] |
TNF-α | Upregulates TIMP-1 production, prevents HSC apoptosis. | [134,135] |
IL-1β,IL-18 | Produced by pro-inflammatory macrophages through activation of the NLRP3 inflammasome. Activates HSCs, upregulates TIMP production. | [136,137] |
IL-13, IL-4 | Produced by M2 macrophages. Promotes the activation of HSCs. | [138] |
MCP1 | Activates CCR2 in Kupffer cells and HSCs. | [139,140] |
CCL2 CCL5 | Produced by macrophages and HSCs. Increases macrophage infiltration and fibrotic phenotype of HSCs. | [141,142] |
CXCL6 | Induces TGF β production by KCs and indirectly promotes fibrosis. | [143] |
Cytokines | Functions | References |
---|---|---|
TNF-α | Inhibit HBV replication, provide antiviral immunity, induce inflammation. | [432,461] |
TGF-β | Impair NK cell function, promote fibrosis and HCC. | [131,132,177] |
IL-10 | Inhibit cytokine production, regulate T cell immunity, develop persistence of HBV infection. | [481,482,484] |
IL-13 | Induce inflammation, liver fibrosis. and cirrhosis. | [471,472] |
IL-6 | Produced by macrophages. Induce inflammation and fibrosis. Inhibit HBV replication; inhibits HBV entry. | [200,202,203] |
IL-18, IL-1β | Pro-inflammatory. Activate HSCs. IL-1β induces the phosphorylation of Smad2/3 to promote the transformation of hepatocytes to EMT. IL-18 rs187238 GG genotype increases the risk of HCC in a healthy population and the risk of cirrhosis in CHB carriers. | [137,199,202] |
IL-17 | Exacerbate inflammation, induce liver fibrosis and cirrhosis. | [436,450,451] |
IL-21 | Produced by activated CD4+ T cells. Activate T and B cells. Maintenance of specific CD8+ T-cell functions and control of viremia. Increased levels may promote cirrhosis and exacerbate liver injury. | [424] |
IL-22 | Inhibit liver inflammation and fibrosis. | [462,463] |
IL-27 | Higher levels in patients with liver cirrhosis or hepatocellular carcinoma. Compensate the function of IL-21 by supporting Tfh-B cell function, required for protective antibody response. | [424] |
IL-33 | Induce liver damage and fibrosis, activate Tfh cells, and enhance humoral immunity; suppress HBV replication. | [426,433,440] |
IL-35 | Development of fibrosis, cirrhosis, and HCC. Inhibit HBV-specific CD8 T cells cytotoxicity. Inhibit cytokines and induce antiviral immunity. | [492,493,494] |
IFN-γ | Antiviral immunity. Inhibit HBV replication; induce inflammation. | [432,434] |
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Tsomidis, I.; Voumvouraki, A.; Kouroumalis, E. Immune Checkpoints and the Immunology of Liver Fibrosis. Livers 2025, 5, 5. https://doi.org/10.3390/livers5010005
Tsomidis I, Voumvouraki A, Kouroumalis E. Immune Checkpoints and the Immunology of Liver Fibrosis. Livers. 2025; 5(1):5. https://doi.org/10.3390/livers5010005
Chicago/Turabian StyleTsomidis, Ioannis, Argyro Voumvouraki, and Elias Kouroumalis. 2025. "Immune Checkpoints and the Immunology of Liver Fibrosis" Livers 5, no. 1: 5. https://doi.org/10.3390/livers5010005
APA StyleTsomidis, I., Voumvouraki, A., & Kouroumalis, E. (2025). Immune Checkpoints and the Immunology of Liver Fibrosis. Livers, 5(1), 5. https://doi.org/10.3390/livers5010005