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Cited by 92Redox biology and oxidative stressNeutrophil, Myeloperoxidase and Oxidative MechanismsLiver physiology and pathology

Nadph oxidase 1 in liver macrophages promotes inflammation and tumor development in mice

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Liang, Shuang, Ma, Hsiao-Yen, Zhong, Zhenyu, Dhar, Debanjan, Liu, Xiao, Xu, Jun, Koyama, Yukinori, Nishio, Takahiro +12 more·2019·Gastroenterology
DOI 10.1053/j.gastro.2018.11.019PMC PMC6409207
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Abstract

Background & Aims Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen. Methods Fourteen-day-old Nox1 –/– mice, Nox4 –/– mice, Nox1 –/– Nox4 –/– (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes ( Nox1 ΔHep ), hepatic stellate cells ( Nox1 ΔHep ), or macrophages ( Nox1 ΔMac ). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8–12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots. Results Nox4 –/– mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1 –/– mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1 ΔHep and Nox1 ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1 ΔMac developed fewer and smaller tumors, similar to Nox1 –/– mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1 –/– or Nox1 ΔMac , mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1 ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle. Conclusions In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.

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Crossref · 10.1053/j.gastro.2018.11.019

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  • Recognition of DAMPs released from damaged hepatocytes increases total cellular ROS levels and induces ERK1/2-mediated expression of IL-6 and TNF in BMDM.

    “Mechanistically, recognition of damage-associated molecular patterns (DAMP) released from damaged hepatocytes in vitro increased total cellular ROS levels (see also Section 5.1) and induced extracellular signal-regulated kinases 1/2 (ERK1/2)-mediated expression of IL-6 and TNF in BMDM.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [319]

  • Liver macrophages, identified via cell-type specific Nox1 deletion, promote a proinflammatory liver environment, hepatocyte proliferation, tumor development, and liver damage, while Nox1 deletion in hepatocytes and bile duct cells has no effect.

    “Liver macrophages were identified via cell-type specific Nox1 deletion as promoters of a proinflammatory liver environment, hepatocyte proliferation, tumor development and liver damage, while Nox1 deletion in hepatocytes and bile duct cells had no effect.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [319]

  • Nox1-deficient BMDM show no ROS production and no expression of cytokines.

    “Nox1-deficient BMDM showed no ROS production and no expression of cytokines, nicely corroborating the in vivo findings.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [319]

  • Nox1-deficient, but not Nox4-deficient, animals show strongly reduced tumor numbers and size and reduced liver damage in a hepatocellular carcinoma model.

    “Nox1-deficient, but not Nox4-deficient, animals showed strongly reduced tumor numbers and size and reduced liver damage.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [319]

  • Nox1/Nox4 double-deficient mice resemble Nox1-deficient mice, excluding an interconnection between the two Nox enzymes.

    “Nox1/Nox4 double-deficient mice resembled Nox1-deficient mice excluding an interconnection between the two Nox enzymes.”

    From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [319]

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Authors
Liang, S., Ma, H.-Y., Zhong, Z., Dhar, D., Liu, X., Xu, J., Koyama, Y., Nishio, T., Karin, D., Karin, G., Mccubbin, R., Zhang, C., Hu, R., Yang, G., Chen, L., Ganguly, S., Lan, T., Karin, M., Kisseleva, T., & Brenner, D. A.
Affiliations
  • University of California San Diego (US)
  • Kyoto University (JP)
  • Shandong University (CN)
  • Sun Yat-sen University (CN)
  • Guangdong Pharmaceutical University (CN)
Corresponding author
  • Kisseleva, Tatiana
  • Brenner, David A.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2019-03
Volume
156
Issue
4
Pages
1156-1172.e6
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2018.11.019
PMC
PMC6409207
OpenAlex
W2900859474
Cited by
92
References
72
Citations by year
2026: 7 · 2025: 5 · 2024: 12 · 2023: 14 · 2022: 9 · 2021: 21 · 2020: 15 · 2019: 8 · 2018: 1
FWCI
4.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institutes of Health (R01 DK101737-01A1, U01 AA022614-01A1, R01 DK099205-01A1, P50 AA011999)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
NOX1, NOX4, hepatocellular carcinoma, hepatocarcinogenesis, hepatic macrophages, diethylnitrosamine, oxidative stress, inflammation, TNF-α, interleukin-6, STAT3 phosphorylation, hepatic stellate cells
MeSH terms
Alarmins, NADPH Oxidase 1, NADPH Oxidase 4, Animals, Cell Transformation, Neoplastic, Cells, Cultured, Diethylnitrosamine, Enzyme Inhibitors, Hepatitis, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Experimental, Macrophages, Male, Mice, Inbred C57BL, Necrosis, Tumor Necrosis Factor-alpha, Interleukin-6, Culture Media, Conditioned, Mice, Knockout, Hepatocytes, Tumor Burden, Cell Proliferation, STAT3 Transcription Factor, Mice, Hepatic Stellate Cells

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