Macrophages coordinate immune response to laser-induced injury via extracellular traps
Abstract Background Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remode...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-024-03064-0 |
| _version_ | 1797247144547057664 |
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| author | Federica M. Conedera Despina Kokona Martin S. Zinkernagel Jens V. Stein Charles P. Lin Clemens Alt Volker Enzmann |
| author_facet | Federica M. Conedera Despina Kokona Martin S. Zinkernagel Jens V. Stein Charles P. Lin Clemens Alt Volker Enzmann |
| author_sort | Federica M. Conedera |
| collection | DOAJ |
| description | Abstract Background Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury. Methods Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina. Results Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer. Conclusions Our data offer novel insights into innate immunity's role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration. |
| first_indexed | 2024-04-24T19:54:01Z |
| format | Article |
| id | doaj.art-916c1fd49e544c4fb67ae384fc06888f |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-24T19:54:01Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-916c1fd49e544c4fb67ae384fc06888f2024-03-24T12:28:04ZengBMCJournal of Neuroinflammation1742-20942024-03-0121112010.1186/s12974-024-03064-0Macrophages coordinate immune response to laser-induced injury via extracellular trapsFederica M. Conedera0Despina Kokona1Martin S. Zinkernagel2Jens V. Stein3Charles P. Lin4Clemens Alt5Volker Enzmann6Department of Oncology, Microbiology and Immunology, University of FribourgDepartment of Ophthalmology, Bern University Hospital and Department of BioMedical Research, University of BernDepartment of Ophthalmology, Bern University Hospital and Department of BioMedical Research, University of BernDepartment of Oncology, Microbiology and Immunology, University of FribourgCenter for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical SchoolCenter for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Ophthalmology, Bern University Hospital and Department of BioMedical Research, University of BernAbstract Background Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury. Methods Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina. Results Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer. Conclusions Our data offer novel insights into innate immunity's role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration.https://doi.org/10.1186/s12974-024-03064-0Innate immune cellsExtracellular trapsMicrogliaMacrophagesLeukocyte infiltrationRetinal laser-injury |
| spellingShingle | Federica M. Conedera Despina Kokona Martin S. Zinkernagel Jens V. Stein Charles P. Lin Clemens Alt Volker Enzmann Macrophages coordinate immune response to laser-induced injury via extracellular traps Journal of Neuroinflammation Innate immune cells Extracellular traps Microglia Macrophages Leukocyte infiltration Retinal laser-injury |
| title | Macrophages coordinate immune response to laser-induced injury via extracellular traps |
| title_full | Macrophages coordinate immune response to laser-induced injury via extracellular traps |
| title_fullStr | Macrophages coordinate immune response to laser-induced injury via extracellular traps |
| title_full_unstemmed | Macrophages coordinate immune response to laser-induced injury via extracellular traps |
| title_short | Macrophages coordinate immune response to laser-induced injury via extracellular traps |
| title_sort | macrophages coordinate immune response to laser induced injury via extracellular traps |
| topic | Innate immune cells Extracellular traps Microglia Macrophages Leukocyte infiltration Retinal laser-injury |
| url | https://doi.org/10.1186/s12974-024-03064-0 |
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