Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma
Abstract Background Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously...
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doaj-1d88fd54288e4ead90e9c80f9e2ea71f2020-11-25T00:13:23ZengBMCMolecular Neurodegeneration1750-13262019-01-0114112310.1186/s13024-018-0303-3Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucomaPete A. Williams0Catherine E. Braine1Krishnakumar Kizhatil2Nicole E. Foxworth3Nicholas G. Tolman4Jeffrey M. Harder5Rebecca A. Scott6Gregory L. Sousa7Alyssa Panitch8Gareth R. Howell9Simon W. M. John10The Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryDepartment of Materials Science and Engineering, University of DelawareThe Jackson LaboratoryDepartment of Biomedical Engineering, University of CaliforniaThe Jackson LaboratoryThe Jackson LaboratoryAbstract Background Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. Methods To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes. Based on their pro-inflammatory molecular signatures, we hypothesized and confirmed that monocyte-platelet interactions occur in glaucomatous tissue. Furthermore, to test monocyte function we used two approaches to inhibit their entry into the optic nerve head: (1) treatment with DS-SILY, a peptidoglycan that acts as a barrier to platelet adhesion to the vessel wall and to monocytes, and (2) genetic targeting of Itgam (CD11b, an immune cell receptor that enables immune cell extravasation). Results Monocyte specific RNA-sequencing identified novel neuroinflammatory pathways early in glaucoma pathogenesis. Targeting these processes pharmacologically (DS-SILY) or genetically (Itgam / CD11b knockout) reduced monocyte entry and provided neuroprotection in DBA/2 J eyes. Conclusions These data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury.http://link.springer.com/article/10.1186/s13024-018-0303-3GlaucomaRetinal ganglion cellOptic nerveMonocyteVascular leakageExtravasation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pete A. Williams Catherine E. Braine Krishnakumar Kizhatil Nicole E. Foxworth Nicholas G. Tolman Jeffrey M. Harder Rebecca A. Scott Gregory L. Sousa Alyssa Panitch Gareth R. Howell Simon W. M. John |
spellingShingle |
Pete A. Williams Catherine E. Braine Krishnakumar Kizhatil Nicole E. Foxworth Nicholas G. Tolman Jeffrey M. Harder Rebecca A. Scott Gregory L. Sousa Alyssa Panitch Gareth R. Howell Simon W. M. John Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma Molecular Neurodegeneration Glaucoma Retinal ganglion cell Optic nerve Monocyte Vascular leakage Extravasation |
author_facet |
Pete A. Williams Catherine E. Braine Krishnakumar Kizhatil Nicole E. Foxworth Nicholas G. Tolman Jeffrey M. Harder Rebecca A. Scott Gregory L. Sousa Alyssa Panitch Gareth R. Howell Simon W. M. John |
author_sort |
Pete A. Williams |
title |
Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma |
title_short |
Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma |
title_full |
Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma |
title_fullStr |
Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma |
title_full_unstemmed |
Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma |
title_sort |
inhibition of monocyte-like cell extravasation protects from neurodegeneration in dba/2j glaucoma |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2019-01-01 |
description |
Abstract Background Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. Methods To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes. Based on their pro-inflammatory molecular signatures, we hypothesized and confirmed that monocyte-platelet interactions occur in glaucomatous tissue. Furthermore, to test monocyte function we used two approaches to inhibit their entry into the optic nerve head: (1) treatment with DS-SILY, a peptidoglycan that acts as a barrier to platelet adhesion to the vessel wall and to monocytes, and (2) genetic targeting of Itgam (CD11b, an immune cell receptor that enables immune cell extravasation). Results Monocyte specific RNA-sequencing identified novel neuroinflammatory pathways early in glaucoma pathogenesis. Targeting these processes pharmacologically (DS-SILY) or genetically (Itgam / CD11b knockout) reduced monocyte entry and provided neuroprotection in DBA/2 J eyes. Conclusions These data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury. |
topic |
Glaucoma Retinal ganglion cell Optic nerve Monocyte Vascular leakage Extravasation |
url |
http://link.springer.com/article/10.1186/s13024-018-0303-3 |
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