Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation
Inflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR). However, therapeutic targeting of inflammation has been hampered by a lack of under...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01733/full |
| _version_ | 1819199475305938944 |
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| author | Audrey Bernut Audrey Bernut Catherine A. Loynes Catherine A. Loynes R. Andres Floto R. Andres Floto Stephen A. Renshaw Stephen A. Renshaw |
| author_facet | Audrey Bernut Audrey Bernut Catherine A. Loynes Catherine A. Loynes R. Andres Floto R. Andres Floto Stephen A. Renshaw Stephen A. Renshaw |
| author_sort | Audrey Bernut |
| collection | DOAJ |
| description | Inflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR). However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used a CFTR-depleted zebrafish larva, as an innovative in vivo vertebrate model, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF. We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the molecule Tanshinone IIA successfully accelerates inflammation resolution and improves tissue repair in CF animal. Our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes. |
| first_indexed | 2024-12-23T03:16:55Z |
| format | Article |
| id | doaj.art-1b5406e344db44bb8d40108e85458ff5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T03:16:55Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1b5406e344db44bb8d40108e85458ff52022-12-21T18:02:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-07-011110.3389/fimmu.2020.01733562603Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile InflammationAudrey Bernut0Audrey Bernut1Catherine A. Loynes2Catherine A. Loynes3R. Andres Floto4R. Andres Floto5Stephen A. Renshaw6Stephen A. Renshaw7Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United KingdomBateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield, United KingdomDepartment of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United KingdomBateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield, United KingdomMolecular Immunity Unit, Department of Medicine, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical, Cambridge, United KingdomCambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, United KingdomDepartment of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United KingdomBateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield, United KingdomInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR). However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used a CFTR-depleted zebrafish larva, as an innovative in vivo vertebrate model, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF. We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the molecule Tanshinone IIA successfully accelerates inflammation resolution and improves tissue repair in CF animal. Our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.https://www.frontiersin.org/article/10.3389/fimmu.2020.01733/fullcystic fibrosisCFTRneutrophilic inflammationapoptosistissue repairneutrophil reverse migration |
| spellingShingle | Audrey Bernut Audrey Bernut Catherine A. Loynes Catherine A. Loynes R. Andres Floto R. Andres Floto Stephen A. Renshaw Stephen A. Renshaw Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation Frontiers in Immunology cystic fibrosis CFTR neutrophilic inflammation apoptosis tissue repair neutrophil reverse migration |
| title | Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation |
| title_full | Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation |
| title_fullStr | Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation |
| title_full_unstemmed | Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation |
| title_short | Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation |
| title_sort | deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation |
| topic | cystic fibrosis CFTR neutrophilic inflammation apoptosis tissue repair neutrophil reverse migration |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01733/full |
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