Suppression of inner blood-retinal barrier breakdown and pathogenic Müller glia activation in ischemia retinopathy by myeloid cell depletion.

Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2004-

Blood-Retinal Barrier*/drug effects ; Blood-Retinal Barrier*/metabolism ; Blood-Retinal Barrier*/pathology ; Ependymoglial Cells*/metabolism ; Ependymoglial Cells*/drug effects ; Ependymoglial Cells*/pathology ; Myeloid Cells*/metabolism ; Myeloid Cells*/drug effects; Animals ; Mice ; Mice, Inbred C57BL ; Retinal Diseases/pathology ; Retinal Diseases/metabolism ; Ischemia/metabolism ; Reperfusion Injury/metabolism ; Reperfusion Injury/pathology ; Male ; Microglia/metabolism ; Microglia/drug effects ; Organic Chemicals

Ischemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction of the neurovascular unit including neurons, glia, and vascular cells is now understood to underlie this process, there is a need for fuller elucidation of the underlying events in BRB dysfunction in ischemic disease, including a systematic analysis of myeloid cells and exploration of cellular cross-talk. We used an approach for microglia depletion with the CSF-1R inhibitor PLX5622 (PLX) in the retinal ischemia-reperfusion (IR) model. Under non-IR conditions, PLX treatment successfully depleted microglia in the retina. PLX suppressed the microglial activation response following IR as well as infiltration of monocyte-derived macrophages. This occurred in association with reduction of retinal expression of chemokines including CCL2 and the inflammatory adhesion molecule ICAM-1. In addition, there was a marked suppression of retinal neuroinflammation with reduction in expression of IL-1b, IL-6, Ptgs2, TNF-a, and Angpt2, a protein that regulates BRB permeability. PLX treatment significantly suppressed inner BRB breakdown following IR, without an appreciable effect on neuronal dysfunction. A translatomic analysis of Müller glial-specific gene expression in vivo using the Ribotag approach demonstrated a strong suppression of Müller cell expression of multiple pro-inflammatory genes following PLX treatment. Co-culture studies of Müller cells and microglia demonstrated that activated microglia directly upregulates Müller cell-expression of these inflammatory genes, indicating Müller cells as a downstream effector of myeloid cells in retinal IR. Co-culture studies of these two cell types with endothelial cells demonstrated the ability of both activated microglia and Müller cells to compromise EC barrier function. Interestingly, quiescent Müller cells enhanced EC barrier function in this co-culture system. Together this demonstrates a pivotal role for myeloid cells in inner BRB breakdown in the setting of ischemia-associated disease and indicates that myeloid cells play a major role in iBRB dysregulation, through direct and indirect effects, while Müller glia participate in amplifying the neuroinflammatory effect of myeloid cells.
(© 2024. The Author(s).)

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R01 EY022683 United States EY NEI NIH HHS; EY022683 United States EY NEI NIH HHS

Keywords: Blood-retinal barrier; Csf1r; Macrophages; Microglia; Müller glia; Neuroinflammation

0 (PLX5622)
0 (Organic Chemicals)

Date Created: 20240824 Date Completed: 20240824 Latest Revision: 20240830

20240830

PMC11344463

10.1186/s12974-024-03190-9

39182142