Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation
Abstract Background Microglia-associated inflammation is closely related to the pathogenesis of various retinal diseases such as uveitis and diabetic retinopathy, which are associated with increased vascular permeability. In this study, we investigated the effect of systemic lipopolysaccharide (LPS)...
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| Format: | Article |
| Language: | English |
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BMC
2018-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1373-4 |
| _version_ | 1811326001359093760 |
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| author | Despina Kokona Andreas Ebneter Pascal Escher Martin S. Zinkernagel |
| author_facet | Despina Kokona Andreas Ebneter Pascal Escher Martin S. Zinkernagel |
| author_sort | Despina Kokona |
| collection | DOAJ |
| description | Abstract Background Microglia-associated inflammation is closely related to the pathogenesis of various retinal diseases such as uveitis and diabetic retinopathy, which are associated with increased vascular permeability. In this study, we investigated the effect of systemic lipopolysaccharide (LPS) exposure to activation and proliferation of retinal microglia /macrophages. Methods Balb/c and Cx3cr1 gfp/+ mice were challenged with LPS (1 mg/kg) daily for four consecutive days. For microglia depletion, mice were treated with colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 1 week before the first LPS challenge and until the end of the experiment. In vivo imaging of the retina was performed on days 4 and 7 after the first LPS challenge, using optical coherence tomography and fluorescein angiography. Flow cytometry analysis, retinal whole mount, and retinal sections were used to investigate microglia and macrophage infiltration and proliferation after LPS challenge. Cytokines were analyzed in the blood as well as in the retina. Data analysis was performed using unpaired t tests, repeated measures one-way ANOVA, or ordinary one-way ANOVA followed by Tukey’s post hoc analysis. Kruskal-Wallis test followed by Dunn’s multiple comparison tests was used for the analysis of non-normally distributed data. Results Repeated LPS challenge led to activation and proliferation of retinal microglia, infiltration of monocyte-derived macrophages into the retina, and breakdown of the blood-retina barrier (BRB) accompanied by accumulation of sub-retinal fluid. Using in vivo imaging, we show that the breakdown of the BRB is highly reproducible but transitory. Acute but not chronic systemic exposure to LPS triggered a robust release of inflammatory mediators in the retina with minimal effects in the blood plasma. Inhibition of the CSF-1R by PLX5622 resulted in depletion of retinal microglia, suppression of cytokine production in the retina, and prevention of BRB breakdown. Conclusions These findings suggest that microglia/macrophages play an important role in the pathology of retinal disorders characterized by breakdown of the BRB, and suppression of their activation may be a potential therapeutic target for such retinopathies. |
| first_indexed | 2024-04-13T14:42:17Z |
| format | Article |
| id | doaj.art-302393bf013a41d9a3974d69946b40b5 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T14:42:17Z |
| publishDate | 2018-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-302393bf013a41d9a3974d69946b40b52022-12-22T02:42:51ZengBMCJournal of Neuroinflammation1742-20942018-12-0115111810.1186/s12974-018-1373-4Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammationDespina Kokona0Andreas Ebneter1Pascal Escher2Martin S. Zinkernagel3Department of Ophthalmology, Inselspital, Bern University Hospital, and University of BernDepartment of Ophthalmology, Inselspital, Bern University Hospital, and University of BernDepartment of Ophthalmology, Inselspital, Bern University Hospital, and University of BernDepartment of Ophthalmology, Inselspital, Bern University Hospital, and University of BernAbstract Background Microglia-associated inflammation is closely related to the pathogenesis of various retinal diseases such as uveitis and diabetic retinopathy, which are associated with increased vascular permeability. In this study, we investigated the effect of systemic lipopolysaccharide (LPS) exposure to activation and proliferation of retinal microglia /macrophages. Methods Balb/c and Cx3cr1 gfp/+ mice were challenged with LPS (1 mg/kg) daily for four consecutive days. For microglia depletion, mice were treated with colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 1 week before the first LPS challenge and until the end of the experiment. In vivo imaging of the retina was performed on days 4 and 7 after the first LPS challenge, using optical coherence tomography and fluorescein angiography. Flow cytometry analysis, retinal whole mount, and retinal sections were used to investigate microglia and macrophage infiltration and proliferation after LPS challenge. Cytokines were analyzed in the blood as well as in the retina. Data analysis was performed using unpaired t tests, repeated measures one-way ANOVA, or ordinary one-way ANOVA followed by Tukey’s post hoc analysis. Kruskal-Wallis test followed by Dunn’s multiple comparison tests was used for the analysis of non-normally distributed data. Results Repeated LPS challenge led to activation and proliferation of retinal microglia, infiltration of monocyte-derived macrophages into the retina, and breakdown of the blood-retina barrier (BRB) accompanied by accumulation of sub-retinal fluid. Using in vivo imaging, we show that the breakdown of the BRB is highly reproducible but transitory. Acute but not chronic systemic exposure to LPS triggered a robust release of inflammatory mediators in the retina with minimal effects in the blood plasma. Inhibition of the CSF-1R by PLX5622 resulted in depletion of retinal microglia, suppression of cytokine production in the retina, and prevention of BRB breakdown. Conclusions These findings suggest that microglia/macrophages play an important role in the pathology of retinal disorders characterized by breakdown of the BRB, and suppression of their activation may be a potential therapeutic target for such retinopathies.http://link.springer.com/article/10.1186/s12974-018-1373-4InflammationRetinaMicrogliaBlood-retina barrierCSF-1RSub-retinal fluid |
| spellingShingle | Despina Kokona Andreas Ebneter Pascal Escher Martin S. Zinkernagel Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation Journal of Neuroinflammation Inflammation Retina Microglia Blood-retina barrier CSF-1R Sub-retinal fluid |
| title | Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation |
| title_full | Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation |
| title_fullStr | Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation |
| title_full_unstemmed | Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation |
| title_short | Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation |
| title_sort | colony stimulating factor 1 receptor inhibition prevents disruption of the blood retina barrier during chronic inflammation |
| topic | Inflammation Retina Microglia Blood-retina barrier CSF-1R Sub-retinal fluid |
| url | http://link.springer.com/article/10.1186/s12974-018-1373-4 |
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