دورية أكاديمية
أعرض في EDS

Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.

التفاصيل البيبلوغرافية
العنوان: Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.
المؤلفون: Gaul S; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; Universität Leipzig, Klinik und Poliklinik für Kardiologie, Leipzig, Germany., Leszczynska A; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Alegre F; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain., Kaufmann B; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Johnson CD; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; University of California Irvine, Irvine, CA, USA., Adams LA; Medical School, University of Western Australia, Perth, Australia., Wree A; Department of Hepatology and Gastroenterology, Charité, Campus Virchow Klinikum and Charité, Universitätsmedizin Berlin, Berlin, Germany., Damm G; Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Leipzig, Germany., Seehofer D; Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Leipzig, Germany., Calvente CJ; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Povero D; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA., Kisseleva T; Department of Surgery, University of California San Diego, La Jolla, CA, USA., Eguchi A; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; Department of Gastroenterology and Hepatology, Mie University, Tsu, Mie, Japan., McGeough MD; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Hoffman HM; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Pelegrin P; Biomedical Research Institute of Murcia, Clinical University Hospital Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain., Laufs U; Universität Leipzig, Klinik und Poliklinik für Kardiologie, Leipzig, Germany., Feldstein AE; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. Electronic address: afeldstein@ucsd.edu.
المصدر: Journal of hepatology [J Hepatol] 2021 Jan; Vol. 74 (1), pp. 156-167. Date of Electronic Publication: 2020 Aug 04.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Amsterdam : Elsevier
Original Publication: Copehnagen : Munksgaard International Publishers, [c1984-
مواضيع طبية MeSH: Hepatocytes*/metabolism , Hepatocytes*/pathology , Liver Cirrhosis*/immunology , Liver Cirrhosis*/metabolism, Inflammasomes/*metabolism , Interleukin-1beta/*metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism , Pyroptosis/*immunology, Animals ; Caspase 1/metabolism ; Hepatic Stellate Cells/metabolism ; Hepatic Stellate Cells/pathology ; Humans ; Mice ; Mice, Inbred NOD ; Non-alcoholic Fatty Liver Disease/metabolism ; Non-alcoholic Fatty Liver Disease/pathology ; Protein Translocation Systems/metabolism ; Reactive Oxygen Species/metabolism
مستخلص: Background & Aims: Increased hepatocyte death contributes to the pathology of acute and chronic liver diseases. However, the role of hepatocyte pyroptosis and extracellular inflammasome release in liver disease is unknown.
Methods: We used primary mouse and human hepatocytes, hepatocyte-specific leucine 351 to proline Nlrp3 KI CreA mice, and Gsdmd KO mice to investigate pyroptotic cell death in hepatocytes and its impact on liver inflammation and damage. Extracellular NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes were isolated from mutant NLRP3-YFP HEK cells and internalisation was studied in LX2 and primary human hepatic stellate cells. We also examined a cohort of 154 adult patients with biopsy-proven non-alcoholic fatty liver disease (Sir Charles Gairdner Hospital, Nedlands, Western Australia).
Results: We demonstrated that primary mouse and human hepatocytes can undergo pyroptosis upon NLRP3 inflammasome activation with subsequent release of NLRP3 inflammasome proteins that amplify and perpetuate inflammasome-driven fibrogenesis. Pyroptosis was inhibited by blocking caspase-1 and gasdermin D activation. The activated form of caspase-1 was detected in the livers and in serum from patients with non-alcoholic steatohepatitis and correlated with disease severity. Nlrp3 KI CreA mice showed spontaneous liver fibrosis under normal chow diet, and increased sensitivity to liver damage and inflammation after treatment with low dose lipopolysaccharide. Mechanistically, hepatic stellate cells engulfed extracellular NLRP3 inflammasome particles leading to increased IL-1β secretion and α-smooth muscle actin expression. This effect was abrogated when cells were pre-treated with the endocytosis inhibitor cytochalasin B.
Conclusions: These results identify hepatocyte pyroptosis and release of inflammasome components as a novel mechanism to propagate liver injury and liver fibrosis development.
Lay Summary: Our findings identify a novel mechanism of inflammation in the liver. Experiments in cell cultures, mice, and human samples show that a specific form of cell death, called pyroptosis, leads to the release of complex inflammatory particles, the NLRP3 inflammasome, from inside hepatocytes into the extracellular space. From there they are taken up by other cells and thereby mediate inflammatory and pro-fibrogenic stress signals. The discovery of this mechanism may lead to novel treatments for chronic liver diseases in the future.
Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.
(Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
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معلومات مُعتمدة: U01 AA029019 United States AA NIAAA NIH HHS; R01 AA028134 United States AA NIAAA NIH HHS; P30 DK048522 United States DK NIDDK NIH HHS; R01 DK113592 United States DK NIDDK NIH HHS; R01 DK111866 United States DK NIDDK NIH HHS; R01 DK099205 United States DK NIDDK NIH HHS; R01 AA028550 United States AA NIAAA NIH HHS; R01 HL140898 United States HL NHLBI NIH HHS; R01 AA024206 United States AA NIAAA NIH HHS; R01 DK101737 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: ASC; Fibrosis; Hepatocytes; Inflammasome; Liver; NASH; NLRP3; Pyroptosis; Specks
المشرفين على المادة: 0 (Inflammasomes)
0 (Interleukin-1beta)
0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (Protein Translocation Systems)
0 (Reactive Oxygen Species)
EC 3.4.22.36 (Caspase 1)
تواريخ الأحداث: Date Created: 20200809 Date Completed: 20220114 Latest Revision: 20240326
رمز التحديث: 20240326
مُعرف محوري في PubMed: PMC7749849
DOI: 10.1016/j.jhep.2020.07.041
PMID: 32763266
قاعدة البيانات: MEDLINE
الوصف
تدمد:1600-0641
DOI:10.1016/j.jhep.2020.07.041