Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury
Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macroph...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00626/full |
| _version_ | 1818850840825298944 |
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| author | Nadine Graubardt Nadine Graubardt Milena Vugman Odelia Mouhadeb Odelia Mouhadeb Gabriele Caliari Metsada Pasmanik-Chor Debby Reuveni Ehud Zigmond Eli Brazowski Eyal David Lousie Chappell-Maor Steffen Jung Chen Varol Chen Varol |
| author_facet | Nadine Graubardt Nadine Graubardt Milena Vugman Odelia Mouhadeb Odelia Mouhadeb Gabriele Caliari Metsada Pasmanik-Chor Debby Reuveni Ehud Zigmond Eli Brazowski Eyal David Lousie Chappell-Maor Steffen Jung Chen Varol Chen Varol |
| author_sort | Nadine Graubardt |
| collection | DOAJ |
| description | Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6Chi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14+ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA-seq-based transcriptome profiling of neutrophils from Ly6Chi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p ≤ 0.05). In the absence of Ly6Chi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6Chi monocytes differentiated into ephemeral Ly6Clo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6Chi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6Chi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance. |
| first_indexed | 2024-12-19T06:55:32Z |
| format | Article |
| id | doaj.art-f14c89b1e5a647ac81222f098b893c48 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T06:55:32Z |
| publishDate | 2017-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f14c89b1e5a647ac81222f098b893c482022-12-21T20:31:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-06-01810.3389/fimmu.2017.00626263829Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver InjuryNadine Graubardt0Nadine Graubardt1Milena Vugman2Odelia Mouhadeb3Odelia Mouhadeb4Gabriele Caliari5Metsada Pasmanik-Chor6Debby Reuveni7Ehud Zigmond8Eli Brazowski9Eyal David10Lousie Chappell-Maor11Steffen Jung12Chen Varol13Chen Varol14The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Immunology, Weizmann Institute of Science, Rehovot, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Clinical Microbiology and Immunology, The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelBioinformatics Unit, G. S. Wise Faculty of Life Science, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Immunology, Weizmann Institute of Science, Rehovot, IsraelDepartment of Immunology, Weizmann Institute of Science, Rehovot, IsraelDepartment of Immunology, Weizmann Institute of Science, Rehovot, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Clinical Microbiology and Immunology, The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelMonocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6Chi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14+ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA-seq-based transcriptome profiling of neutrophils from Ly6Chi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p ≤ 0.05). In the absence of Ly6Chi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6Chi monocytes differentiated into ephemeral Ly6Clo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6Chi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6Chi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00626/fullmacrophagesmonocytesneutrophilsdrug-induced liver injuryliver immunology |
| spellingShingle | Nadine Graubardt Nadine Graubardt Milena Vugman Odelia Mouhadeb Odelia Mouhadeb Gabriele Caliari Metsada Pasmanik-Chor Debby Reuveni Ehud Zigmond Eli Brazowski Eyal David Lousie Chappell-Maor Steffen Jung Chen Varol Chen Varol Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury Frontiers in Immunology macrophages monocytes neutrophils drug-induced liver injury liver immunology |
| title | Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury |
| title_full | Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury |
| title_fullStr | Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury |
| title_full_unstemmed | Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury |
| title_short | Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury |
| title_sort | ly6chi monocytes and their macrophage descendants regulate neutrophil function and clearance in acetaminophen induced liver injury |
| topic | macrophages monocytes neutrophils drug-induced liver injury liver immunology |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00626/full |
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