Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure
Abstract
Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti–granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1–signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9−/− mice). Conclusion: Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.
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Extracellular mitochondria have been identified in damaged tissues, diverse inflammatory conditions, and in the blood of critical care patients.
“Extracellular mitochondria have been identified in damaged tissues (8, 18–20); diverse inflammatory conditions (11, 12, 14, 21–24); and in the blood of critical care patients (22).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [19]
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References 43 · Cited by 332
- Authors
- Marques, P. E., Amaral, S. S., Pires, D. A., Nogueira, L. L., Soriani, F. M., Lima, B. H. F., Lopes, G. A. O., Russo, R. C., Ávila, T. V., Melgaço, J. G., Oliveira, A. G., Pinto, M. A., Lima, C. X., De Paula, A. M., Cara, D. C., Leite, M. F., Teixeira, M. M., & Menezes, G. B.
- Affiliations
- Universidade Federal de Minas Gerais (BR)
- Instituto Oswaldo Cruz (BR)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Menezes, Gustavo Batista
- ORCID
- Venue
- Hepatology
- Published
- 2012-11
- Volume
- 56
- Issue
- 5
- Pages
- 1971-1982
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2079326842
- Cited by
- 332
- References
- 43
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 21 · 2023: 25 · 2022: 24 · 2021: 30 · 2020: 20 · 2019: 34 · 2018: 36 · 2017: 33 · 2016: 16 · 2015: 19 · 2014: 22 · 2013: 17 · 2012: 6
- FWCI
- 23.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Arca - Repositório Institucional da Fiocruz (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- acetaminophen toxicity, acute liver failure, neutrophil infiltration, CXCR2, FPR1, mitochondrial DNA, formyl peptides, liver necrosis, systemic inflammation, lung injury, TLR9
- MeSH terms
- Acetaminophen, Acute-Phase Reaction, Adolescent, Adult, Analysis of Variance, Animals, Cell Movement, Child, DNA, Mitochondrial, Female, Humans, Liver, Male, Mice, Inbred C57BL, Middle Aged, Necrosis, Neutrophils, Signal Transduction, Interleukin-8, Liver Failure, Acute, Mice, Knockout, Systemic Inflammatory Response Syndrome, Coculture Techniques, Chemokines, Receptors, Interleukin-8B, Mitochondrial Proteins, Receptors, Formyl Peptide, Toll-Like Receptor 9, Mice, Acute Lung Injury, Young Adult, Hep G2 Cells
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