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Abstract #79921 Published in IGR 20-2
Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma
Williams PA; Braine CE; Kizhatil K; Foxworth NE; Tolman NG; Harder JM; Scott RA; Sousa GL; Panitch A; Howell GR; John SWMMolecular Neurodegeneration 2019; 14: 6
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.
Full article
Classification:
11.8 Neuroprotection (Part of: 11 Medical treatment)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
3.8 Pharmacology (Part of: 3 Laboratory methods)