Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease
Abstract Background Diabetic retinopathy and retinal vein occlusion are vision threatening retinal vascular diseases. Current first-line therapy targets the vascular component, but many patients are treatment-resistant due to unchecked inflammation. Non-invasive inflammatory imaging biomarkers are a...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02562-3 |
| _version_ | 1798042673485971456 |
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| author | Amrita Rajesh Steven Droho Jeremy A. Lavine |
| author_facet | Amrita Rajesh Steven Droho Jeremy A. Lavine |
| author_sort | Amrita Rajesh |
| collection | DOAJ |
| description | Abstract Background Diabetic retinopathy and retinal vein occlusion are vision threatening retinal vascular diseases. Current first-line therapy targets the vascular component, but many patients are treatment-resistant due to unchecked inflammation. Non-invasive inflammatory imaging biomarkers are a significant unmet clinical need for patients. Imaging of macrophage-like cells on the surface of the retina using clinical optical coherence tomography (OCT) is an emerging field. These cells are increased in patients with retinal vascular disease, and could be a potential inflammatory biomarker. However, since OCT is limited by an axial resolution of 5–10 microns, the exact location and identity of these retinal cells is currently unknown. Methods We performed OCT followed by confocal immunofluorescence in wild-type mice to identify macrophages within 5–10 microns of the vitreoretinal interface. Next, we used Cx3cr1 CreER/+; Rosa26 zsGreen/+ mice to fate map retinal surface macrophages. Using confocal immunofluorescence of retinal sections and flatmounts, we quantified IBA1+ Tmem119 +CD169neg microglia, IBA1+ Tmem119 negCD169neg perivascular macrophages, and IBA1+ Tmem119 negCD169+ vitreal hyalocytes. Finally, we modeled neuroinflammation with CCL2 treatment and characterized retinal surface macrophages using flow cytometry, OCT, and confocal immunofluorescence. Results We were able to detect IBA1+ macrophages within 5–10 microns of the vitreoretinal interface in wild-type mice using OCT followed by confirmatory confocal immunofluorescence. Retinal surface macrophages were 83.5% GFP+ at Week 1 and 82.4% GFP+ at Week 4 using fate mapping mice. At steady state, these macrophages included 82% IBA1+ Tmem119 +CD169neg microglia, 9% IBA1+ Tmem119 negCD169+ vitreal hyalocytes, and 9% IBA1+ Tmem119 negCD169neg perivascular macrophages. After CCL2-driven neuroinflammation, many Ly6C+ cells were detectable on the retinal surface using OCT followed by confocal immunofluorescence. Conclusions Macrophages within close proximity to the vitreoretinal interface are self-renewing cells, and predominantly microglia with minor populations of perivascular macrophages and vitreal hyalocytes at steady state. In the context of neuroinflammation, monocytes and monocyte-derived macrophages are a significant component of retinal surface macrophages. Human OCT-based imaging of retinal surface macrophages is a potential biomarker for inflammation during retinal vascular disease. |
| first_indexed | 2024-04-11T22:38:44Z |
| format | Article |
| id | doaj.art-908ce95a7c3c4cd38873781db7bd3201 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T22:38:44Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-908ce95a7c3c4cd38873781db7bd32012022-12-22T03:59:07ZengBMCJournal of Neuroinflammation1742-20942022-08-0119111410.1186/s12974-022-02562-3Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular diseaseAmrita Rajesh0Steven Droho1Jeremy A. Lavine2Department of Ophthalmology, Feinberg School of Medicine, Northwestern UniversityDepartment of Ophthalmology, Feinberg School of Medicine, Northwestern UniversityDepartment of Ophthalmology, Feinberg School of Medicine, Northwestern UniversityAbstract Background Diabetic retinopathy and retinal vein occlusion are vision threatening retinal vascular diseases. Current first-line therapy targets the vascular component, but many patients are treatment-resistant due to unchecked inflammation. Non-invasive inflammatory imaging biomarkers are a significant unmet clinical need for patients. Imaging of macrophage-like cells on the surface of the retina using clinical optical coherence tomography (OCT) is an emerging field. These cells are increased in patients with retinal vascular disease, and could be a potential inflammatory biomarker. However, since OCT is limited by an axial resolution of 5–10 microns, the exact location and identity of these retinal cells is currently unknown. Methods We performed OCT followed by confocal immunofluorescence in wild-type mice to identify macrophages within 5–10 microns of the vitreoretinal interface. Next, we used Cx3cr1 CreER/+; Rosa26 zsGreen/+ mice to fate map retinal surface macrophages. Using confocal immunofluorescence of retinal sections and flatmounts, we quantified IBA1+ Tmem119 +CD169neg microglia, IBA1+ Tmem119 negCD169neg perivascular macrophages, and IBA1+ Tmem119 negCD169+ vitreal hyalocytes. Finally, we modeled neuroinflammation with CCL2 treatment and characterized retinal surface macrophages using flow cytometry, OCT, and confocal immunofluorescence. Results We were able to detect IBA1+ macrophages within 5–10 microns of the vitreoretinal interface in wild-type mice using OCT followed by confirmatory confocal immunofluorescence. Retinal surface macrophages were 83.5% GFP+ at Week 1 and 82.4% GFP+ at Week 4 using fate mapping mice. At steady state, these macrophages included 82% IBA1+ Tmem119 +CD169neg microglia, 9% IBA1+ Tmem119 negCD169+ vitreal hyalocytes, and 9% IBA1+ Tmem119 negCD169neg perivascular macrophages. After CCL2-driven neuroinflammation, many Ly6C+ cells were detectable on the retinal surface using OCT followed by confocal immunofluorescence. Conclusions Macrophages within close proximity to the vitreoretinal interface are self-renewing cells, and predominantly microglia with minor populations of perivascular macrophages and vitreal hyalocytes at steady state. In the context of neuroinflammation, monocytes and monocyte-derived macrophages are a significant component of retinal surface macrophages. Human OCT-based imaging of retinal surface macrophages is a potential biomarker for inflammation during retinal vascular disease.https://doi.org/10.1186/s12974-022-02562-3BiomarkersDiabetic retinopathyInflammationMacrophageOptical coherence tomographyRetinal vein occlusion |
| spellingShingle | Amrita Rajesh Steven Droho Jeremy A. Lavine Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease Journal of Neuroinflammation Biomarkers Diabetic retinopathy Inflammation Macrophage Optical coherence tomography Retinal vein occlusion |
| title | Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease |
| title_full | Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease |
| title_fullStr | Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease |
| title_full_unstemmed | Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease |
| title_short | Macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease |
| title_sort | macrophages in close proximity to the vitreoretinal interface are potential biomarkers of inflammation during retinal vascular disease |
| topic | Biomarkers Diabetic retinopathy Inflammation Macrophage Optical coherence tomography Retinal vein occlusion |
| url | https://doi.org/10.1186/s12974-022-02562-3 |
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