Document Type

Article

Publication Date

1-22-2019

Keywords

JMG

JAX Source

Mol Neurodegener 2019 Jan 22; 14(1):6

PMID

30670050

DOI

https://doi.org/10.1186/s13024-018-0303-3

Grant

EY011721,EY021525

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.

Comments

The Authors would like to thank Electron Microscopy, Flow Cytometry, Histology, and Gene Expression Services at The Jackson Laboratory, Rick Libby for careful reading of the manuscript and discussion, Mimi de Vries for assistance with organizing and mouse colonies, Brynn Cardozo and Trip Freeburg for colony maintenance, Jocelyn Thomas for blood collections, Philipp Tauber for assistance with immunofluorescence, and Amy Bell for intraocular pressure measurements.

This open access article is licensed under a Creative Commons Attribution 4.0 International License

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