دورية أكاديمية
Gpbar-1/cAMP/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome.
| العنوان: | Gpbar-1/cAMP/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome. |
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| المؤلفون: | Zhuang L; The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China; Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China., Jia N; Department of Hepatobiliary Surgery, Kunshan First People's Hospital affiliated to Jiangsu University, Kunshan, Jiangsu 215300, China., Zhang L; The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China., Zhang Q; Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China., Antwi SO; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA., Sartorius K; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; School of Laboratory Medicine and Molecular Sciences, College of Health Sciences, University of Kwazulu-Natal, Durban 4041, South Africa; UKZN Gastrointestinal Cancer Research Unit, University of Kwazulu-Natal, Durban 4041, South Africa., Wu K; The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China., Sun D; The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China. Electronic address: sdldoctor@163.com., Xi D; Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China. Electronic address: xi-dong76@hotmail.com., Lu Y; Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; Department of Hepatopancreatobiliary surgery, The First Affiliated Hospital of Soochow University, Suzhou 215100, China. Electronic address: lyj0001@suda.edu.cn. |
| المصدر: | Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Aug; Vol. 1870 (6), pp. 167266. Date of Electronic Publication: 2024 May 26. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam : Elsevier |
| مواضيع طبية MeSH: | NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein*/genetics , Inflammasomes*/metabolism , Cyclic AMP-Dependent Protein Kinases*/metabolism , Cyclic AMP*/metabolism , Signal Transduction* , Cholestasis*/metabolism , Cholestasis*/pathology , Receptors, G-Protein-Coupled*/metabolism , Receptors, G-Protein-Coupled*/genetics, Animals ; Humans ; Mice ; Male ; Kupffer Cells/metabolism ; Mice, Inbred C57BL ; Female ; Macrophages/metabolism ; Macrophages/immunology ; Liver/metabolism ; Liver/pathology ; Liver/injuries ; Lipopolysaccharides/toxicity ; Adult ; Middle Aged |
| مستخلص: | Acute cholestatic liver injury (ACLI) is a disease associated with bile duct obstruction that causes liver inflammation and apoptosis. Although G protein-coupled bile acid receptor1 (Gpbar-1) has diverse metabolic roles, its involvement in ACLI-associated immune activation remains unclear. Liver tissues and blood samples from 20 patients with ACLI and 20 healthy individuals were analyzed using biochemical tests, H&E staining, western blotting, and immunohistochemistry to verify liver damage and expression of Gpbar-1. The expression of Gpbar-1, cAMP/PKA signaling, and the NLRP3 inflammasome was tested in wild-type (WT) and Gpbar-1 knockdown (si-Gpbar-1) mice with ACLI induced by bile duct ligation (BDL) and in primary Kupffer cells (KCs) with or without Gpbar-1-siRNA. The results showed that total bile acids and Gpbar-1 expressions were elevated in patients with ACLI. Gpbar-1 knockdown significantly worsened BDL-induced acute hepatic damage, inflammation, and liver apoptosis in vivo. Knockdown of Gpbar-1 heightened KC sensitivity to lipopolysaccharide (LPS) stimulation. Gpbar-1 activation inhibited LPS-induced pro-inflammatory responses in normal KCs but not in Gpbar-1-knockdown KCs. Notably, NLRP3-ASC inflammasome expression was effectively enhanced by Gpbar-1 deficiency. Additionally, Gpbar-1 directly increased intracellular cAMP levels and PKA phosphorylation, thus disrupting the NLRP3-ASC inflammasome. The pro-inflammatory characteristic of Gpbar-1 deficiency was almost neutralized by the NLRP3 inhibitor CY-09. In vitro, M1 polarization was accelerated in LPS-stimulated Gpbar-1-knockdown KCs. Therapeutically, Gpbar-1 deficiency exacerbated BDL-induced ACLI, which could be rescued by inhibition of the NLRP3-ASC inflammasome. Our study reveal that Gpbar-1 may act as a novel immune-mediated regulator of ACLI by inhibiting the NLRP3-ASC inflammasome. Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. All authors agree to the author list. (Copyright © 2024 Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Acute cholestatic liver injury; G protein-coupled bile acid receptor 1; Inflammation response; Macrophage; NLRP3-ASC inflammasome |
| المشرفين على المادة: | 0 (NLR Family, Pyrin Domain-Containing 3 Protein) 0 (Inflammasomes) EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) E0399OZS9N (Cyclic AMP) 0 (Receptors, G-Protein-Coupled) 0 (GPBAR1 protein, human) 0 (Gpbar1 protein, mouse) 0 (Nlrp3 protein, mouse) 0 (NLRP3 protein, human) 0 (Lipopolysaccharides) |
| تواريخ الأحداث: | Date Created: 20240528 Date Completed: 20240615 Latest Revision: 20240910 |
| رمز التحديث: | 20240911 |
| DOI: | 10.1016/j.bbadis.2024.167266 |
| PMID: | 38806072 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1879-260X |
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| DOI: | 10.1016/j.bbadis.2024.167266 |