Apoptosis recognition receptors regulate skin tissue repair in mice
Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a m...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/86269 |
| _version_ | 1827576737789116416 |
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| author | Olivia Justynski Kate Bridges Will Krause Maria Fernanda Forni Quan M Phan Teresa Sandoval-Schaefer Kristyn Carter Diane E King Henry C Hsia Michael I Gazes Steven D Vyce Ryan R Driskell Kathryn Miller-Jensen Valerie Horsley |
| author_facet | Olivia Justynski Kate Bridges Will Krause Maria Fernanda Forni Quan M Phan Teresa Sandoval-Schaefer Kristyn Carter Diane E King Henry C Hsia Michael I Gazes Steven D Vyce Ryan R Driskell Kathryn Miller-Jensen Valerie Horsley |
| author_sort | Olivia Justynski |
| collection | DOAJ |
| description | Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1+ macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for efferocytosis pathway genes and display altered efferocytosis signaling via the receptor Axl and its ligand Gas6. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients. |
| first_indexed | 2024-03-08T21:16:43Z |
| format | Article |
| id | doaj.art-dbdf124a3b954f59bcd564236e200881 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T21:16:43Z |
| publishDate | 2023-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-dbdf124a3b954f59bcd564236e2008812023-12-21T16:24:43ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.86269Apoptosis recognition receptors regulate skin tissue repair in miceOlivia Justynski0https://orcid.org/0000-0002-0774-5983Kate Bridges1https://orcid.org/0000-0003-3642-7068Will Krause2https://orcid.org/0000-0001-7585-5749Maria Fernanda Forni3https://orcid.org/0000-0002-3335-9023Quan M Phan4Teresa Sandoval-Schaefer5Kristyn Carter6Diane E King7Henry C Hsia8Michael I Gazes9Steven D Vyce10Ryan R Driskell11https://orcid.org/0000-0001-7673-2564Kathryn Miller-Jensen12https://orcid.org/0000-0002-7233-0100Valerie Horsley13https://orcid.org/0000-0002-1254-5839Dept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United StatesDept. of Biomedical Engineering, Yale University, New Haven, United StatesDept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United StatesDept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United StatesWashington State University, SMB, Pullman, United StatesDept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United StatesDept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United StatesSunnycrest Bioinformatics, Flemington, United StatesDept. of Surgery (Plastic), Yale School of Medicine, New Haven, United StatesDept of Podiatric Surgery, Yale New Haven Hospital, New Haven, United StatesDept of Podiatric Surgery, Yale New Haven Hospital, New Haven, United StatesWashington State University, SMB, Pullman, United StatesDept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United States; Dept. of Biomedical Engineering, Yale University, New Haven, United StatesDept. of Molecular Cellular and Developmental Biology, Yale University, New Haven, United States; Dept. of Dermatology, Yale School of Medicine, New Haven, United StatesApoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1+ macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for efferocytosis pathway genes and display altered efferocytosis signaling via the receptor Axl and its ligand Gas6. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.https://elifesciences.org/articles/86269wound healingapoptosisefferocytosisskinrepair |
| spellingShingle | Olivia Justynski Kate Bridges Will Krause Maria Fernanda Forni Quan M Phan Teresa Sandoval-Schaefer Kristyn Carter Diane E King Henry C Hsia Michael I Gazes Steven D Vyce Ryan R Driskell Kathryn Miller-Jensen Valerie Horsley Apoptosis recognition receptors regulate skin tissue repair in mice eLife wound healing apoptosis efferocytosis skin repair |
| title | Apoptosis recognition receptors regulate skin tissue repair in mice |
| title_full | Apoptosis recognition receptors regulate skin tissue repair in mice |
| title_fullStr | Apoptosis recognition receptors regulate skin tissue repair in mice |
| title_full_unstemmed | Apoptosis recognition receptors regulate skin tissue repair in mice |
| title_short | Apoptosis recognition receptors regulate skin tissue repair in mice |
| title_sort | apoptosis recognition receptors regulate skin tissue repair in mice |
| topic | wound healing apoptosis efferocytosis skin repair |
| url | https://elifesciences.org/articles/86269 |
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