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
Liver Bacterial Dysbiosis With Non-Tuberculosis Mycobacteria Occurs in SIV-Infected Macaques and Persists During Antiretroviral Therapy
Fisher, B. S., Fancher, K. A., Gustin, A. T., Fisher, C., Wood, M. P., Gale, M., Burwitz, B. J., Smedley, J. V., Klatt, N. R., Derby, N. R., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.793842 · Cited by 5
“Neutrophils are rapidly recruited to sites of acute inflammation, though the method of recruitment of these cells to the liver is not well known (21, 22).”
Background
Identification of polyunsaturated fatty acids related key modules and genes in metabolic dysfunction-associated fatty liver disease using WGCNA analysis
Xiao, C., Chen, S., Yang, C., Liu, J. Y., & Yu, M. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.951224 · Cited by 5
“, 2014) secreted by hepatocytes or activated neutrophils further enhance injury to hepatic tissue, which leads to MAFLD (Machado and Diehl, 2016; Koyama and Brenner, 2017; Schuster et al., 2018).”
Background
Diagnostic and Prognostic Value of Monocyte-to-Lymphocyte Ratio and Red Cell Distribution Width to Lymphocyte Ratio in Primary Biliary Cholangitis
Jiang, Y., Wang, J., Wu, H., Zhou, W., Li, S., & Jin, M. Y. (2023) · The Turkish Journal of Gastroenterology · doi:10.5152/tjg.2023.21768 · Cited by 5
Migration inhibitory factor and cluster of differentiation 74‐mediated dendritic cell apoptosis exacerbates acute acetaminophen‐induced liver injury
Wu, Z., He, L., Huang, J., Liao, B., & Xiao, F. (2023) · Immunity Inflammation and Disease · doi:10.1002/iid3.840 · Cited by 5
Metabolic dysfunction-associated steatotic liver disease is associated with the risk of severe liver fibrosis in pediatric population
Li, W., Jiang, L.-N., Li, M.-L., Lin, C., Zhu, L., Zhao, B.-K., Liu, Y.-S., Li, Y., Jiang, Y.-Y., Liu, S.-H., et al. (2025) · Gastroenterology Report · doi:10.1093/gastro/goaf056 · Cited by 6
“Histological evidence of steatohepatitis has been proven to be a risk for worsening hepatic outcomes [18, 19].”
Diagnostic value of serum Golgi protein 73 in liver fibrosis and inflammation in patients with autoimmune hepatitis
Zhang, Y., Xu, A., Jin, Y., Gao, J., & He, J. (2025) · Medicine · doi:10.1097/md.0000000000043064 · Cited by 4
Homeostatic remodeling platform for reprogramming Iron Intraspatial orientation to reverse liver fibrosis.
Duan, B.-W., Liu, Y.-J., Hong, H.-Y., Fang, Y.-F., Qiao, J.-B., Yang, J.-S., Xing, L., & Jiang, H.-L. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114117 · Cited by 4
Novel Aurone Derivative Ameliorates MASH Lipid Metabolism via the AMPK-ACC-PPARα Axis
Bai, S., Zou, Y., Zhang, W., Yu, J., Qie, Z., Liu, Z., Yu, P., Xiang, C., & Teng, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211099 · Cited by 6
“Chronic liver inflammation is not only a hallmark of MASH but also a critical pathological mechanism driving hepatic fibrosis [70,71].”
Palmitic acid induced the onset of lipotoxicity in a HepaSH-on-chip model with raised of H2O2 and IL-6, and altered p38/MAPK & JAK/STAT pathways
Wang, H., Poulain, S., Cao, W., Arakawa, H., Kim, S. H., Kato, Y., Nishikawa, M., Sakai, Y., & Leclerc, É. (2025) · Toxicology · doi:10.1016/j.tox.2025.154345 · Cited by 4
Ameliorative efficacy of Syzygium aromaticum ethanolic extract and Silymarin® upon carbon tetrachloride-induced liver fibrosis: antioxidant, antibacterial and anti-inflammatory activities
El‐Fakharany, E. M., El-Sayed, M. H., Ali, H. M., Omar, S. M., Sayed, A. M., Atwa, A. M., Alfaifi, M. Y., Shati, A. A., Elbehairi, S. E. I., Alrayes, Z. R., et al. (2025) · Medical Oncology · doi:10.1007/s12032-025-03100-w · Cited by 4
The gene regulatory networks shaping macrophage plasticity and altered function in fibrosis
Kolostyák, Z., & Nagy, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1767954 · Cited by 5
Loss of immunometabolic adaptability in MASH: gut-derived signals drive macrophage reprogramming and fibrosis
Li, Y. C., Hu, Y., He, Y. M., Yang, Y., Xue, D., Xue, E., Jia, J., Zhang, W., & Wang, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1793092 · Cited by 4
IgA-enriched phenotype predicts liver-related events in MASLD
Kimura, T., Wakabayashi, S., Iwadare, T., Kondo, S., Okumura, T., Kobayashi, H., Yamashita, Y., Kamijo, Y., Fujita, K., Nakajima, T., et al. (2026) · Journal of Hepatology · doi:10.1016/j.jhep.2026.06.044 · Cited by 4
Liver Fibrosis is Associated with Clinical Outcomes in Patients with Intracerebral Hemorrhage
Wang, J., Bian, L., Wang, A., Zhang, X., Wang, D., Jiang, R., Wang, W., Ju, Y., Lu, J., & Zhao, X. (2022) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s375532 · Cited by 4
“Conclusion: Our study suggests that liver fibrosis defined by a FIB-4 score ≥2.67 is associated with poor clinical outcomes and lower survival rates in patients with mild to moderate ICH.”
BackgroundInfluential
Association between low-normal thyroid function and advanced liver fibrosis in metabolic dysfunction-associated fatty liver disease patients: a retrospective cohort study
Li, Z., Wu, X., Chen, Z., Wei, X., & Chen, W. (2023) · Gastroenterology report · doi:10.1093/gastro/goad076 · Cited by 4
NADPH oxidase 4-SH3 domain-containing YSC84-like 1 complex participates liver inflammation and fibrosis
Hur, Y. K., Lee, H., Yoo, J.-Y., Park, Y. N., Lee, I. H., & Bae, Y. S. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.12.021 · Cited by 4
Inhibitory effects of umbelliferone on carbon tetrachloride-induced hepatic fibrosis in rats through the TGF‑β1‑Smad signaling pathway
Liang, L., Dong, Z., Shen, Z., Zang, Y., Yang, W., Wu, L., & Bao, L. (2025) · Molecular Medicine Reports · doi:10.3892/mmr.2025.13536 · Cited by 4
“Effects of UMB on inflammation levels. inflammatory responses activate HScs, which regulate immune responses by secreting chemokines and cytokines, or transform into myofibroblasts that produce matrix, advancing liver fibrosis progression (25).”
Mannosylated neutrophil vesicles targeting macrophages alleviate liver inflammation by delivering CRISPR/Cas9 RNPs
Wu, D., Shu, H., Zhang, M., Wei, X., Ji, J., Shen, H., Zhang, H., Xie, L., Zhou, L., Yang, L. F., et al. (2025) · Theranostics · doi:10.7150/thno.107791 · Cited by 4
“Inflammatory liver diseases, including fulminant hepatitis (FH) and metabolic dysfunction-associated steatohepatitis (MASH), are among the leading causes of irreversible liver diseases and progressive fibrosis [2].”
Management of Acute Fatty Liver of Pregnancy: A Retrospective Study of 12 Cases Compared With Data in the Literature
Maalbi, O., Elachhab, N., Abdelmajid, E., Arfaoui, M., Hindi, S., Lahbabi, S., Oudghiri, N., & Tachinante, R. (2025) · Cureus · doi:10.7759/cureus.85753 · Cited by 4
“Furthermore, a deficiency in long-chain fatty acylhydroxy-CoA dehydrogenase (LCHAD), an autosomal recessive disorder, has been associated with AFLP, potentially leading to severe acute maternal liver failure by exposing the liver to inflammation and fibrosis [7-9].”
Acute liver disorders in the third trimester— AFLP , HELLP and infectious hepatitis—update on pathology, diagnosis and management
Chilaka, V. N., Bashir, M., Ngatchu, T., Ahmed, B., & Konje, J. C. (2025) · The Obstetrician & Gynaecologist · doi:10.1111/tog.12989 · Cited by 4
Dopamine receptor D1-mediated suppression of liver fibrosis via Hippo/Yes-associated protein 1 signaling in levodopa treatment
Wang, H.-Y., Qi, M.-M., Zhang, K., Zhu, Y.-Z., & Zhang, J. (2025) · World Journal of Gastroenterology · doi:10.3748/wjg.v31.i34.108617 · Cited by 4
Potential therapeutic targets and biological mechanisms of Centella asiatica on hepatic fibrosis: a study of network pharmacology
Yuli, F., & Yin, X. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-2253 · Cited by 4
“The central link is focused on the activation of hepatic stellate cells (HSCs), which leads to diffuse and excessive deposition of ECM, resulting in fibrosis formation (8,9).”
Background
CD38 Inhibition Protects Fructose-Induced Toxicity in Primary Hepatocytes
Lee, S. H., Choi, S., Park, S., Hwang, Y., Son, Y., & KANG, Y. Y. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0045 · Cited by 5
“Hepatic inflammation and injury are hallmarks of NASH and are key contributors to liver cirrhosis through the activation of collagen-producing stellate cells (Koyama and Brenner, 2017; Krenkel et al., 2018).”
Background
DA-6034 ameliorates hepatic steatosis and inflammation in high fat diet-induced obese mice
Kim, H. M., Kwon, M. H., Lee, E. S., Ha, K. B., & Chung, C. H. (2024) · Journal of Yeungnam Medical Science · doi:10.12701/jyms.2023.01389 · Cited by 4
“The liver plays a crucial role in glucose homeostasis in the body; however, its function is reduced by lipid accumulation in the liver According to recent studies, the accumulated fat accelerates inflammation by increasing immune cell accumulation and proinflammatory cytokine secretion [3].”
Background
Structure-function analysis of time-resolved immunological phases in metabolic dysfunction-associated fatty liver disease (MASH) comparing the NIF mouse model to human MASH
Schmidt-Christensen, A., Eriksson, G., Laprade, W. M., Pirzamanbein, B., Hörnberg, M., Linde, K., Nilsson, J., Skarsfeldt, M. A., Leeming, D. J., Mokso, R., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-73150-z · Cited by 4
Human Liver MSCs Retain Their Basic Cellular Properties in Chronically Inflamed Liver Tissue
Kim, Y. S., Lupatov, A. Y., Burunova, V. V., Bagmet, N. N., Chardarov, N. K., Malov, S. L., Kholodenko, R. V., Шатверян, Г. А., Manukyan, G. V., Yarygin, K. N., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413374 · Cited by 4
Utilizing ionic liquid-dispersive liquid-liquid microextraction coupled with HPLC for the determination of anthraquinones in Folium Sennae
Cai, Y., Zheng, N., Wang, Y., Wu, Y., Xv, W., Jin, Z. Y., & Xia, X. (2025) · Journal of Food Composition and Analysis · doi:10.1016/j.jfca.2025.107421 · Cited by 4
Network pharmacology-based investigation of the pharmacological mechanisms of diosgenin in nonalcoholic steatohepatitis
Gu, P., Chen, J., Xin, J., Chen, H., Zhang, R., Chen, D., Zhang, Y., & Shao, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-95154-z · Cited by 4
Effects of 3-indoleacrylic acid on alleviating lipopolysaccharide-induced liver inflammatory damage in laying hens
Zhang, Q., Wang, Y., Wang, Y., Yuan, J., Wang, Y., Zeng, Y., Zhang, H., Yang, H., Ma, Q., Shi, D., et al. (2025) · Poultry Science · doi:10.1016/j.psj.2025.105307 · Cited by 5
“This finding aligns with previous studies showing that LPS induces apoptosis through caspase activation and the mitochondrial pathway (Chen and Nu ˜ nez, 2010; Koyama and Brenner, 2017).”
Prevention of Liver Fibrosis and Hepatocellular Carcinoma Using Antiplatelet Drugs
Wang, R.-J., Wang, J., Zhang, X., Yue, Y., Shen, B., & Zhang, Y. (2025) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000002219 · Cited by 4
Salvianolic Acid B Attenuates Liver Fibrosis via Suppression of Glycolysis-Dependent m1 Macrophage Polarization
Song, H., Li, Z.-W., Xu, W., Tan, Y., Kuang, M., Pei, G., & Wang, Z. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47080598 · Cited by 4
“These cells exhibit remarkable plasticity in response to injury signals and can adapt their polarization and can either promote restoration of tissue integrity following acute injury or, in case of chronic injury, contribute to CLD progression [5].”
Influential
The Lymphatic Headmaster of the Mast Cell-Related Splanchnic Inflammation in Portal Hypertension
Aller, M., Blanco‐Rivero, J., Arias, N., Santamarı́a, L., & Árias, J. (2019) · Cells · doi:10.3390/cells8070658 · Cited by 4
“Therefore, the ethopathogenic factor most relevant to liver disease that worsens the splanchnic lymphangiogenic disfunction secondary to portal hypertension would be the hepatic insufficiency [44].”
Background
Long Noncoding RNA LL35/Falcor Regulates Expression of Transcription Factor Foxa2 in Hepatocytes in Normal and Fibrotic Mouse Liver
Sergeeva, O. V., Korinfskaya, S., Kurochkin, I. I., & Zatsepin, T. S. (2019) · Acta Naturae · doi:10.32607/20758251-2019-11-3-66-74 · Cited by 4
Reversine and herbal Xiang–Sha–Liu–Jun–Zi decoction ameliorate thioacetamide-induced hepatic injury by regulating the RelA/NF-κB/caspase signaling pathway
Mai, Z.-H., Huang, Y. G., Huang, D., Huang, Z., He, Z., Li, P., Zhang, S., Weng, J., & Gu, W. (2020) · Open Life Sciences · doi:10.1515/biol-2020-0059 · Cited by 4
[Pathogenic role of NDUFA13 inactivation in spontaneous hepatitis in mice and the mechanism].
Xu, X., Li, R., Zeng, X. Y., Wang, X., Xue, B., Huang, D., & Huang, Y. (2021) · Europe PMC (PubMed Central) · doi:10.12122/j.issn.1673-4254.2021.01.07 · Cited by 4
Transforming growth factor-beta and liver injury in an arginine vasopressin-induced pregnant rat model
Govender, N., Ramdin, S., Reddy, R., & Naicker, T. (2021) · Daehan saengsik uihak hoeji/Clinical and experimental reproductive medicine · doi:10.5653/cerm.2020.04035 · Cited by 4
“It is believed that hepatic injury elevates transforming growth factor beta (TGF-β) gene expression [6].”
Background
Hepatitis C virus treatment with direct‐acting antivirals induces rapid changes in the hepatic proteome
Ball, L. E., Agana, B. A., Comte‐Walters, S., Rockey, D. C., Masur, H., Kottilil, S., & Meissner, E. G. (2021) · Journal of Viral Hepatitis · doi:10.1111/jvh.13593 · Cited by 4
Rational Design, Synthesis and Activities of Phenanthrene Derivatives Against Hepatic Fibrosis
Li, J., Feng, W., Dai, R., & Li, B. (2022) · Fitoterapia · doi:10.1016/j.fitote.2022.105176 · Cited by 4
Non-alcoholic fatty liver disease - opportunities for personalized treatment and drug development
Kemas, A. M., Youhanna, S. C., & Lauschke, V. M. (2022) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2022.2053285 · Cited by 4
“beyond the scope of this article, we refer the interested reader to recent excellent reviews on this topic [40,41].”
Background

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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