Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis
Abstract Chronic liver diseases are highly linked with mitochondrial dysfunction and macrophage infiltration. Mallory-Denk bodies (MDBs) are protein aggregates associated with hepatic inflammation, and MDBs pathogenesis could be induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (D...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s12967-024-05999-7 |
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| author | Zixuan Fang Bei Zhong Yi Shi Wanmei Zhou Maoping Huang Samuel W. French Xiaoping Tang Hui Liu |
| author_facet | Zixuan Fang Bei Zhong Yi Shi Wanmei Zhou Maoping Huang Samuel W. French Xiaoping Tang Hui Liu |
| author_sort | Zixuan Fang |
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| description | Abstract Chronic liver diseases are highly linked with mitochondrial dysfunction and macrophage infiltration. Mallory-Denk bodies (MDBs) are protein aggregates associated with hepatic inflammation, and MDBs pathogenesis could be induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Here, we investigate the macrophage heterogeneity and the role of macrophage during MDBs pathogenesis on DDC-induced MDBs mouse model by single-nucleus RNA sequencing (snRNA-seq). We defined liver macrophages into four distinct subsets including monocyte-derived macrophages (MDMs) subset and three Kupffer cells (KCs) subsets (Gpnmbhigh KCs, Peam1high KCs, and Gpnmblow Pecam1low KCs). Particularly, we identified a novel Gpnmbhigh KCs subset as lipid-associated macrophage (LAM) with high expression of Trem2, CD63, and CD9. Interestingly, LAM showed a potential immunosuppressive characteristic by expressing anti-inflammatory genes IL-7R during the MDBs formation. Using contact and transwell co-culture systems, the released mtDNA from hepatocytes was found to induce the activation of inflammasome in macrophages. Furthermore, we revealed the damaged DNA could activate the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome and subsequently form apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) specks of liver macrophages. Collectively, our results firstly revealed macrophage heterogeneity and inflammasome activation by mtDNA from injured liver during MDBs pathogenesis, providing crucial understanding of pathogenesis of chronic liver disease. |
| format | Article |
| id | doaj-art-86e1d38a466f4b209e3dc7ad3819492d |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-86e1d38a466f4b209e3dc7ad3819492d2025-01-19T12:37:17ZengBMCJournal of Translational Medicine1479-58762025-01-0123111710.1186/s12967-024-05999-7Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesisZixuan Fang0Bei Zhong1Yi Shi2Wanmei Zhou3Maoping Huang4Samuel W. French5Xiaoping Tang6Hui Liu7The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s hospitalThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s hospitalThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s hospitalThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s hospitalThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s hospitalDepartment of Pathology, Harbor UCLA Medical Center, University of CaliforniaThe State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory DiseaseThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s hospitalAbstract Chronic liver diseases are highly linked with mitochondrial dysfunction and macrophage infiltration. Mallory-Denk bodies (MDBs) are protein aggregates associated with hepatic inflammation, and MDBs pathogenesis could be induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Here, we investigate the macrophage heterogeneity and the role of macrophage during MDBs pathogenesis on DDC-induced MDBs mouse model by single-nucleus RNA sequencing (snRNA-seq). We defined liver macrophages into four distinct subsets including monocyte-derived macrophages (MDMs) subset and three Kupffer cells (KCs) subsets (Gpnmbhigh KCs, Peam1high KCs, and Gpnmblow Pecam1low KCs). Particularly, we identified a novel Gpnmbhigh KCs subset as lipid-associated macrophage (LAM) with high expression of Trem2, CD63, and CD9. Interestingly, LAM showed a potential immunosuppressive characteristic by expressing anti-inflammatory genes IL-7R during the MDBs formation. Using contact and transwell co-culture systems, the released mtDNA from hepatocytes was found to induce the activation of inflammasome in macrophages. Furthermore, we revealed the damaged DNA could activate the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome and subsequently form apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) specks of liver macrophages. Collectively, our results firstly revealed macrophage heterogeneity and inflammasome activation by mtDNA from injured liver during MDBs pathogenesis, providing crucial understanding of pathogenesis of chronic liver disease.https://doi.org/10.1186/s12967-024-05999-7Mallory-denk bodies (MDBs)Lipid-associated macrophageSingle-nucleus RNA-sequencingmtDNAInflammasome |
| spellingShingle | Zixuan Fang Bei Zhong Yi Shi Wanmei Zhou Maoping Huang Samuel W. French Xiaoping Tang Hui Liu Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis Journal of Translational Medicine Mallory-denk bodies (MDBs) Lipid-associated macrophage Single-nucleus RNA-sequencing mtDNA Inflammasome |
| title | Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis |
| title_full | Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis |
| title_fullStr | Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis |
| title_full_unstemmed | Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis |
| title_short | Single-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis |
| title_sort | single cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver mallory denk bodies pathogenesis |
| topic | Mallory-denk bodies (MDBs) Lipid-associated macrophage Single-nucleus RNA-sequencing mtDNA Inflammasome |
| url | https://doi.org/10.1186/s12967-024-05999-7 |
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