Cited by 1,295Liver physiology and pathologyLiver Disease Diagnosis and TreatmentLiver Diseases and Immunity

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Liver inflammation and fibrosis

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Koyama, Yukinori, Brenner, David A.·2017·Journal of Clinical Investigation

DOI 10.1172/jci88881PMC PMC5199698

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Abstract

Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Hepatocyte steatosis is a component of metabolic syndrome and insulin resistance. Hepatic steatosis may be benign or progress to hepatocyte injury and the initiation of inflammation, which activates immune cells. While Kupffer cells are the resident macrophage in the liver, inflammatory cells such as infiltrating macrophages, T lymphocytes, neutrophils, and DCs all contribute to liver inflammation. The inflammatory cells activate hepatic stellate cells, which are the major source of myofibroblasts in the liver. Here we review the initiation of inflammation in the liver, the liver inflammatory cells, and their crosstalk with myofibroblasts.

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Background
Potential Immunotherapy Targets for Liver-Directed Therapies, and the Current Scope of Immunotherapeutics for Liver-Related Malignancies
Charles, J., Vrionis, A., Mansur, A., Mathias, T. J., Shaikh, J., Ciner, A., Jiang, Y., & Nezami, N. (2023) · Cancers · doi:10.3390/cancers15092624 · Cited by 8
“Leptin, platelet-derived growth factor (PDGF), reactive oxygen species (ROS), TGF-β, IL-1, and tumor necrosis factor alpha (TNF-α) secreted within the inflamed hepatic environment transform HSCs into a profibrogenic myofibroblast phenotype [10,11].”
Background
Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH
L’homme, L., Sermikli, B. P., Molendi‐Coste, O., Fleury, S., Quemener, S., Maître, M. L., Joseph, M.-L., Pineau, L., Duhem, C., Gross, B. S., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-77858-6 · Cited by 9
Feasibility of T1 mapping with histogram analysis for the diagnosis and staging of liver fibrosis: Preclinical results
Wang, Q., Liu, H., Zhu, Z.-H., Sheng, Y., Du, Y., Li, Y., Liu, J., Zhang, J., & Xing, W. (2020) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2020.11.006 · Cited by 8
Subclinical Liver Disease Is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies
González‐Cantero, Á., Teklu, M., Sorokin, A. V., Prussick, R. B., Gonzalez-Calvin, J. L., Rodríguez, J. L. M., Patel, N. H., Parel, P. M., Manyak, G. A., Teague, H., et al. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.05.034 · Cited by 8
Recruitment of macrophages and bone marrow stem cells to regenerating liver promoted by sodium phthalhydrazide in mice
Danilova, I. G., Yushkov, B. G., Kazakova, I. A., Belousova, A. V., Минин, А. С., & Abidov, M. T. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.07.086 · Cited by 8
Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis
Wen, F., Xu, A., Wei, W., Yang, S., Xi, Z., Ge, Y., Wu, S., & Ju, Z. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105303 · Cited by 8
“Tissue fibrosis was reported in mice exposed to DOX [21,30], and epithelial-to-mesenchymal transition (EMT) along with endothelial-to-mesenchymal transition (EndoMT) are crucial in excessive myofibroblast generation and progression of fibrosis.”
Background
Mesenchymal stem cell therapy for liver fibrosis need “partner”: Results based on a meta-analysis of preclinical studies
Xu, Y., Wang, X.-S., Zhou, X.-L., Lu, W.-M., Tang, X.-K., Jin, Y., & Ye, J.-S. (2024) · World Journal of Gastroenterology · doi:10.3748/wjg.v30.i32.3766 · Cited by 7
“Examples include interleukins IL-1 β , IL-6, and TGF-β [56,57] are important paracrine signals that promote the activation of HSCs[58].”
The potential health benefits and mechanisms of sesame lignans in age-related diseases
Li, Y., Chang, Y., Zhang, Y., Tu, W., Xu, F., Zhang, L., Wang, X., & Wang, L. (2024) · Food Bioscience · doi:10.1016/j.fbio.2024.105360 · Cited by 7
Association of Systemic Inflammation Response Index with Short-Term All-Cause Mortality in Decompensated Liver Cirrhosis Patients
Cheng, J. M., Ju, H., Wang, G., He, C., & Wang, W. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s476743 · Cited by 7
β-Caryophyllene Ameliorates Thioacetamide-Induced Liver Fibrosis in Rats: A Preventative Approach
Eddin, L. B., Mahgoub, A., Almarzooqi, S. S., Adeghate, E. A., Subramanya, S. B., & Ojha, S. K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178493 · Cited by 7
“Unresolved inflammation is also implicated in liver fibrosis induction, in which levels of various inflammatory mediators are notably increased [35].”
Spermidine enhances macrophages anti-inflammatory and regenerative functions by improving mitochondrial fitness
Liu, R., Cao, L., Zhou, Y., Li, Y., Wang, T., Meng, Z., Yang, T., Feng, C., Yang, Q., Liu, X., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157349 · Cited by 8
Associations between composite systemic inflammation indicators(CAR, CLR, SII, AISI, SIRI, and CALLY) and metabolic dysfunction-associated fatty liver disease (MAFLD): evidence from a two-stage study in China
Zhao, J., Zhou, Q., Wang, Y., Xie, F., & Fan, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1702567 · Cited by 7
Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD
Wang, Q., Li, D., Zhu, J., Zhang, M., Zhang, H., Cao, G., Zhu, L., Shi, Q., Hao, J., Wen, Q., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00846 · Cited by 7
“It is appreciated that multiple concurrent intrahepatic and extrahepatic events contribute to development and progression of NAFLD, including cell senescence, insulin resistance, and immune system dysfunction (6, 7).”
Background
The Yin-Yang functions of macrophages in metabolic disorders
Bai, J., & Liu, F. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac035 · Cited by 7
Deleting Gata4 in hepatocytes promoted the progression of NAFLD via increasing steatosis and apoptosis, and desensitizing insulin signaling
He, L., Wang, X., Ding, Z., Liu, L., Cheng, H., Bily, D., Wu, C., Zhang, K., & Xie, L. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109157 · Cited by 7
Progress in the treatment of acute fatty liver of pregnancy and management of perioperative anesthesia review
Qin, X., Chen, X., Yao, L., Wang, J., & Lin, L. (2023) · Gynecology and Obstetrics Clinical Medicine · doi:10.1016/j.gocm.2023.04.002 · Cited by 9
A new cirrhotic animal protocol combining carbon tetrachloride with methotrexate to address limitations of the currently used chemical-induced models
Mansouri, R. A., Ahmad, A. M., Alshaibi, H. F., Al-Bazi, M. M., Banjabi, A. A., Alsufiani, H. M., Aloqbi, A. A., & Aboubakr, E. M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1201583 · Cited by 7
“It is the final stage of liver fibrosis, which is the buildup of scar tissue in the liver (Koyama and Brenner, 2017; Aboubakr et al., 2022).”
Background
Roles of Human Gut Microbiota in Liver Cirrhosis Risk: A Two-Sample Mendelian Randomization Study
Li, O., Han, X., Kim, D., Yang, F., & Bao, Z. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.11.011 · Cited by 9
Effects of repeated weight cycling on non‐alcoholic steatohepatitis in diet‐induced obese mice
Inia, J. A., de Jong, J. C. B. C., Keijzer, N., Menke, A. L., Princen, H. M. G., Jukema, J. W., & van den Hoek, A. M. (2024) · The FASEB Journal · doi:10.1096/fj.202400167r · Cited by 7
“41,42 This is in line with what we demonstrate in the current study, where we found that repeated weight cycling improved hepatic inflammation although there were no significant effects on hepatic fibrosis.”
Result
Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells
Zhang, L., Tao, M., Zhang, H., Zhang, S., Hou, X., Zong, C., Sun, G., Feng, S., Yan, H., Lü, Y., et al. (2024) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2024.111015 · Cited by 7
Single-cell transcriptomics reveal the microenvironment landscape of perfluorooctane sulfonate-induced liver injury in female mice
He, X., Sun, Z., Sun, J., Chen, Y., Luo, Y., Wang, Z., Linghu, D., Song, M., & Cao, C. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.173562 · Cited by 7
Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications
Zhao, J., Yue, P., Mi, N., Li, M., Fu, W., Zhang, X., Gao, L., Bai, M., Tian, L., Jiang, N., et al. (2024) · Medical Review · doi:10.1515/mr-2024-0029 · Cited by 7
Fully automated hybrid approach on conventional MRI for triaging clinically significant liver fibrosis: A multi‐center cohort study
Zha, J., Xia, T., Chen, Z., Zheng, T., Huang, S., Qian, Y., Zhou, J., Cao, P., Wang, Y., Tang, T., et al. (2024) · Journal of Medical Virology · doi:10.1002/jmv.29882 · Cited by 7
“1,26 The manual segmentation is the simple and basic method, though suffering from poor inter ‐ reader reliability in delimiting ROIs.”
Purinergic Signaling in Non-Parenchymal Liver Cells
Martínez, E. M., Ramírez‐Ledesma, M. G., Vázquez‐Victorio, G., Hernández-Muñoz, R. E., Díaz‐Muñoz, M., & Vázquez‐Cuevas, F. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179447 · Cited by 7
“These cells promote the hepatic extravasation of neutrophils and monocytes, which differentiate into macrophages and magnify the inflammatory response [14].”
Background
A new diethylcarbamazine formulation (NANO-DEC) as a therapeutic tool for hepatic fibrosis
Rodrigues, G. B., Oliveira, E. E., Mendonça, F. J. B., dos Santos, L. A. M., de Oliveira, W. H., de França, M. E. R., Lós, D. B., Gabínio, B. M., & Peixoto, C. A. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.09.010 · Cited by 7
The role of the Notch signaling pathway in liver injury and repair
Yue, Z., Ruan, B., Duan, J., Han, H., & Wang, L. (2018) · Journal of Bio-X Research · doi:10.1097/jbr.0000000000000014 · Cited by 7
Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals
Inoue, T., Iwazaki, N., Araki, T., & Hitotsumachi, H. (2020) · Current Pharmaceutical Biotechnology · doi:10.2174/1389201021666200131123524 · Cited by 7
Protective effects of Longhu Rendan on chronic liver injury and fibrosis in mice
Yang, G., Li, S., Jin, J., Xuan, Y., Ding, L., Huang, M., Liu, J., Wang, B., & Lan, T. (2021) · Liver Research · doi:10.1016/j.livres.2021.05.002 · Cited by 7
A Novel Noninvasive Diagnostic Model of HBV-Related Inflammation in Chronic Hepatitis B Virus Infection Patients With Concurrent Nonalcoholic Fatty Liver Disease
Tao, X., Chen, L., Zhao, Y., Liu, Y., Shi, R., Jiang, B., Mi, Y., & Xu, L. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.862879 · Cited by 7
“Continuous chronic inflammation can cause increased extracellular matrix deposition as well as promote liver fibrosis progression due to myofibroblasts (MF) which are derived from activated hepatic stellate cells (HSC) (23, 24).”
Background
GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt
He, Y., Pei, Y., Liu, K., Liu, L., Tian, Y., Li, H., Cong, M., Liu, T., Ma, H., You, H., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04759-z · Cited by 7
“As an essential fibrogenic cytokine produced by Kupffer cells and liver infiltrating immune cells, transforming growth factor (TGF)-β1 enhances extracellular matrix deposition of hepatic stellate cells, which results in tissue fibrosis/cirrhosis in chronic liver diseases [24].”
Background
A novel matrine derivative, WM130, inhibits activation and movement of human hepatic stellate LX-2 cells by targeting cofilin 1
Xu, Y. Y., Duan, J., Ji, W., Liu, C., Li, X., Wu, Q., Gao, C., & Su, C. (2022) · Cytotechnology · doi:10.1007/s10616-022-00548-w · Cited by 7
“2015; Koyama and Brenner 2017).”
Background
Comparing the Therapeutic Mechanism and Immune Response of Human and Mouse Mesenchymal Stem Cells in Immunocompetent Mice With Acute Liver Failure
Wang, C.-H., Chen, C.-Y., Wang, K., Kao, A., Chen, Y.-J., Lin, P.-H., Chen, M. J., Wu, T.-Y., Cheng, J., Lee, K., et al. (2023) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szac084 · Cited by 7
Macrophages Serve as Bidirectional Regulators and Potential Therapeutic Targets for Liver Fibrosis
Liang, W. H., Huang, X., & Shi, J. (2023) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-023-01173-w · Cited by 8
Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model
Allen, J. N., Zhang, J., Quickel, M. D., Kennett, M. J., Patterson, A. D., & Hankey‐Giblin, P. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00379 · Cited by 7
Declining diagnostic accuracy of non-invasive fibrosis tests is associated with elevated alanine aminotransferase in chronic hepatitis B
Wang, L., Fan, Y., & Dou, X. (2018) · World Journal of Clinical Cases · doi:10.12998/wjcc.v6.i12.521 · Cited by 7
Hepatocarcinoma–intestine–pancreas/pancreatitis-associated protein (HIP/PAP) confers protection against hepatic fibrosis through downregulation of transforming growth factor β receptor II
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Analysis of piRNA expression spectra in a non‑alcoholic fatty liver disease mouse model induced by a methionine‑ and choline‑deficient diet
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14-kDa phosphohistidine phosphatase is a potential therapeutic target for liver fibrosis
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Correlation of effective hepatic blood flow with liver pathology in patients with hepatitis B virus
Shu, X., Sun, H., Yang, X., Jia, Y., Xu, P., Cao, H., & Zhang, K. (2021) · Liver Research · doi:10.1016/j.livres.2021.11.003 · Cited by 7
LncRNA activates immune response against Vibrio anguillarum in the intestine-liver axis of turbot (Scophthalmus maximus L.) by sponging miRNA in a ceRNA regulatory network
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Saturated Fats: Time to Assess Their Beneficial Role in a Healthful Diet
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Authors: Koyama, Y., & Brenner, D. A.
Affiliations: University of California San Diego (US)
Corresponding author: Brenner, David A.
ORCID: Koyama, Yukinori
Brenner, David A.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2017-01-03
Volume: 127
Issue: 1
Pages: 55-64
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci88881
PMC: PMC5199698
OpenAlex: W2562949639
Cited by: 1,295
References: 158
Citations by year: 2026: 139 · 2025: 162 · 2024: 159 · 2023: 171 · 2022: 173 · 2021: 177 · 2020: 151 · 2019: 85 · 2018: 63 · 2017: 13
FWCI: 12.30
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institutes of Health (ES010337, AA011999)
National Institute on Alcohol Abuse and Alcoholism (U01AA021856, P50AA011999)
National Institute of Environmental Health Sciences (P42ES010337)
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords: liver inflammation, liver fibrosis, liver cirrhosis, hepatic steatosis, Kupffer cells, hepatic stellate cells, myofibroblasts, immune cell crosstalk, T cells, neutrophils, dendritic cells, metabolic syndrome, insulin resistance
MeSH terms: Animals, Dendritic Cells, Hepatitis, Humans, Inflammation, Kupffer Cells, Liver, Liver Cirrhosis, Neutrophils, T-Lymphocytes, Hepatic Stellate Cells, Myofibroblasts

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