Journal
MOLECULAR NEURODEGENERATION
Volume 14, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13024-018-0303-3
Keywords
Glaucoma; Retinal ganglion cell; Optic nerve; Monocyte; Vascular leakage; Extravasation; Platelet; Neuroinflammation; RNA-sequencing
Categories
Funding
- Karolinska Institutet
- [EY011721]
- [EY021525]
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BackgroundGlaucoma 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/2J), but their roles, if any, in mediating axon damage remain unclear.MethodsTo 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).ResultsMonocyte 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/2J eyes.ConclusionsThese data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury.
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