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Liver inflammation and fibrosis
Open accessAbstract
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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“A key event in liver fibrogenesis is the activation of quiescent HSCs, which differentiate into myofibroblasts and secrete large amounts of collagen and profibrosis factors.( 71 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [71]
In the citing paper
“A key event in liver fibrogenesis is the activation of quiescent HSCs, which differentiate into myofibroblasts and secrete large amounts of collagen and profibrosis factors.( 71 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [71]
In the citing paper
“Hepatic stellate cells (HSCs) play pivotal roles in the pathological development of liver fibrosis27.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [27]
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“HSC is a highly regulated process involving multiple cytokines and growth factors produced by liver infiltrating immune cells and hepatic cells [64, 65].”
BackgroundIshtiaq, S. M., Rashid, H., Hussain, Z., Arshad, M. I., & Khan, J. A. (2019) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09510-2 · Cited by 66
Sun, L., Ouyang, J., Ma, Y., Zeng, Z., Zeng, C., Zeng, F., & Wu, S. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202100867 · Cited by 66
Zhao, Y., Liu, X., Ding, C., Gu, Y., & Liu, W. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.783886 · Cited by 66
“In addition, studies have shown that inflammatory damage is an important factor leading to many chronic liver diseases, and which is usually accompanied by the development of liver fibrosis, cirrhosis and hepatocellular carcinoma (Koyama and Brenner, 2017).”
BackgroundMeier, R. P. H., Meyer, J., Montanari, E., Lacotte, S., Balaphas, A., Müller, Y. D., Clément, S., Negro, F., Toso, C., Morel, P., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061295 · Cited by 66
“Overall, whether it is clear from numerous previous works that prolonged inflammation can lead to fibrosis [48], our findings along with those of others [24] suggest that this process is not solely driven by a direct effect of IL-1 on HSC.”
ResultRockey, D. C., Du, Q., & Shi, Z. (2019) · American Journal Of Pathology · doi:10.1016/j.ajpath.2019.07.019 · Cited by 72
Multiplexing Nanodrug Ameliorates Liver Fibrosis via ROS Elimination and Inflammation Suppression
Xu, Y., Chen, J., Jiang, W., Zhao, Y., Yang, C., Wu, Y., Li, Q., & Zhu, C. (2021) · Small · doi:10.1002/smll.202102848 · Cited by 65
Sarkar, K., Bank, S., Chatterjee, A., Dutta, K., Das, A., Chakraborty, S., Paul, N., Sarkar, J., De, S., Ghosh, S., et al. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-02015-w · Cited by 67
“On the other hand, liver inflammation also progresses due to this meta-inflammation in obesity leading to non-alcoholic steatohepatitis (NASH) by the involvement of activated Kupffer’s cells and activated macrophage infiltration in the liver [9].”
BackgroundComplement factor H–deficient mice develop spontaneous hepatic tumors
Laskowski, J., Renner, B., Pickering, M. C., Serkova, N. J., Smith-Jones, P. M., Clambey, E. T., Nemenoff, R. A., & Thurman, J. M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci135105 · Cited by 62
“If left unresolved, however, inflammation can damage surrounding tissues, eventually leading to fibrosis, organ failure, and carcinogenesis (1, 2).”
BackgroundAnti-fibrotic treatments for chronic liver diseases: The present and the future
Odagiri, N., Matsubara, T., Sato-Matsubara, M., Fujii, H., Enomoto, M., & Kawada, N. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0187 · Cited by 64
“Hepatocyte cell death caused by chronic liver injury causes inflammatory activity of liver immune cells, predominantly macrophages, leading to an increase in these secretory factors.(17) In addition, pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides released from microbes, DNA, and damaged-ass…”
BackgroundCalcagno, D. M., Chu, A., Gaul, S., Taghdiri, N., Toomu, A., Leszczynska, A., Kaufmann, B. K., Papouchado, B. G., Wree, A., Geisler, L. J., et al. (2022) · Hepatology · doi:10.1002/hep.32320 · Cited by 62
“Acute liver inflammation typically involves the rapid recruitment of neutrophils, yet the specific functions that neutrophils play during liver injury and the signaling mechanisms for neutrophil recruitment are incompletely understood.[36] One study found that liver fibrosis was neither worsened nor ameliorated by dim…”
BackgroundPrevalence and Risk Factors of Metabolic Associated Fatty Liver Disease in Xinxiang, China
Li, H., Guo, M., An, Z., Meng, J., Jiang, J., Song, J., & Wu, W. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17061818 · Cited by 62
“The progressive form of MAFLD is characterized by inflammation, cellular injury, and fibrosis [34], and peripheral blood leukocyte is often increased.”
BackgroundPuengel, T., Krenkel, O., Kohlhepp, M. S., Lefebvre, E. A., Luedde, T., Trautwein, C., & Tacke, F. (2017) · PLoS ONE · doi:10.1371/journal.pone.0184694 · Cited by 62
Potential role of ghrelin in the regulation of inflammation
Ma, Y.-X., Zhang, H., Guo, W., & Yu, L. (2022) · The FASEB Journal · doi:10.1096/fj.202200634r · Cited by 51
Fan, J., Chen, Q., Wei, L., Zhou, X., Wang, R., & Zhang, H. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s179876 · Cited by 60
“Hepatocyte damage promotes secretion of inflammatory cytokines and directly induces HSCs activation.(36) In this study, the mRNA levels of the inflammatory cytokines and biomarkers TGF-β1, Cox-2, TNF-α, IL-6, and IL-1β were significantly increased in the model group, but they were significantly attenuated by AA treatm…”
BackgroundThe effect of emodin on liver disease -- comprehensive advances in molecular mechanisms
Hu, N., Liu, J., Xue, X., & Li, Y. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173269 · Cited by 60
Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation
Wang, S., Zha, L., Cui, X., Yeh, Y., Liu, R., Jing, J., Shi, H., Chen, W., Hanover, J. A., Yin, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202206068 · Cited by 63
Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease
Yang, M., Ma, F., & Guan, M. (2021) · Metabolites · doi:10.3390/metabo11050320 · Cited by 61
“Liver inflammation can lead to fibrosis that may eventually induce cirrhosis [99].”
BackgroundTargeting monocytes/macrophages in fibrosis and cancer diseases: Therapeutic approaches
Conte, E. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108031 · Cited by 61
Owen, N. E., Alexander, G., Sen, S., Bunclark, K., Polwarth, G. J., Pepke‐Żaba, J., Davenport, A. P., Morrell, N. W., & Upton, P. D. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102794 · Cited by 58
“As inflammation is prevalent in liver disease [46], this led us to question whether the plasma samples may contain inflammatory factors that interfere with BMP signalling.”
BackgroundShi, M.-J., Yan, X., Dong, B.-S., Yang, W.-N., Su, S.-B., & Zhang, H. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.112689 · Cited by 58
Li, C., Li, L., Yang, C., Zhong, Y., Wu, D., Shi, L., Chen, L., & Li, Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.09.030 · Cited by 58
The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity
Conn, C. S., Yang, H., Tom, H. J., Ikeda, K., Osés-Prieto, J. A., Vu, H., Oguri, Y., Nair, S., Gill, R. M., Kajimura, S., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00349-z · Cited by 56
An update on animal models of liver fibrosis
Wu, S., Wang, X., Xing, W., Li, F., Liang, M., Li, K., He, Y., & Wang, J. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1160053 · Cited by 71
“It is supposed that fibrosis is promoted by neutrophils through ROS production inducing hepatocyte injury and hepatic stellate cells (HSC) activation (16).”
BackgroundThe Space of Disse: The Liver Hub in Health and Disease
Sanz-García, C., Fernández-Iglesias, A., Gracia-Sancho, J., Arráez-Aybar, L. A., Nevzorova, Y. A., & Cubero, F. J. (2021) · Livers · doi:10.3390/livers1010002 · Cited by 57
“TRAIL-mediated and TNFα-mediated apoptosis of HSCs, expression of MMP by restorative Ly6Clow monocytes and interferon (IFN)γ by NK cells or ER stress are some directions that seem to improve fibrosis resolution [4,5,16].”
BackgroundInfluentialHepatic Stellate Cell: A Double-Edged Sword in the Liver
Luo, N., Li, J., Wei, Y., Lu, J., & Dong, R. (2021) · Physiological Research · doi:10.33549/physiolres.934755 · Cited by 64
Hall, K. C., Bernier, S. G., Jacobson, S., Liu, G., Zhang, P. Y., Sarno, R., Catanzano, V., Currie, M. G., & Masferrer, J. L. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821045116 · Cited by 59
“While many of praliciguat antiinflammatory effects could be mediated by stellate cells, praliciguat may also impact the inflammatory cells involved in liver fibrosis, such as Kupffer cells and infiltrating macrophages or neutrophils (29).”
BackgroundHernández‐Aquino, E., Quezada‐Ramírez, M. A., Silva-Olivares, A., Casas‐Grajales, S., Ramos‐Tovar, E., Flores‐Beltrán, R. E., Segovia, J., Shibayama, M., & Muriel, P. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172730 · Cited by 57
Zadorozhna, M., Gioia, S. D., Conese, M., & Mangieri, D. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05290-0 · Cited by 60
“The inflammatory foci are comprised of lymphocytes, plasma cells, monocytes/macrophages (LY6Chi phenotype) as well as granulocytes [21, 22].”
BackgroundInterplay Between Macrophages and Angiogenesis: A Double-Edged Sword in Liver Disease
Ramírez-Pedraza, M., & Fernández, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02882 · Cited by 60
“Furthermore, KC and bone marrowderived macrophages can be recruited by HSC secretion of adhesion molecules such as vascular cell adhesion molecular1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and E-selectin (37) (Figure 3).”
Background
Metadata
- Authors
- Koyama, Y., & Brenner, D. A.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Brenner, David A.
- Venue
- Journal of Clinical Investigation
- Published
- 2017-01-03
- Volume
- 127
- Issue
- 1
- Pages
- 55-64
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- 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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