Juxtavascular Microglia Scavenge Dying Pericytes and Vascular Smooth Muscle Cells in Diabetic Retinopathy

Tom A Gardiner,Alan W Stitt

doi:10.3390/ijtm2010004

Tom A Gardiner, Alan W Stitt

Open Access

https://doi.org/10.3390/ijtm2010004

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Abstract

Diabetic retinopathy (DR) remains a prevalent complication of diabetes and a major cause of vision loss among the working population. Selective loss of pericytes and vascular smooth muscle cells (SMCs), the mural cells of the retinal blood vessels, is pathognomonic of the vasodegenerative element of diabetic retinopathy, and recent studies suggest a central role for autophagy-dependent cell death in this pathology. Our first study of archival electron micrographs from diabetic donor retina provided evidence for the involvement of autophagy in mural cell death during DR and the current report extends those observations to the fate of mural cell corpses in the vascular wall. Here we show that the efferocytosis, or phagocytic removal of dying mural cells, is carried out by a population of juxtavascular microglia (JVM). This population of microglia are well-characterised in the brain but previously unreported in the retina. We demonstrate that JVM are distinct from perivascular macrophages as they participate in the glia limitans of the retinal vasculature and constitute an integral component of the neurovascular unit of the retina. Importantly, mural cells undergoing active phagocytic engulfment appeared to represent relatively early stages in autophagy-dependent cell death, suggesting that the more degraded pericyte and SMC corpses, known as “ghosts”, have evaded efficient efferocytosis and undergone secondary necrosis. The alternative fates of mural cell corpses in the retinal vasculature may have important implications for inflammatory processes in the vasodegenerative pathology characteristic of DR.

Highlights

Diabetic retinopathy (DR) continues to represent the most common complication of diabetes and a major cause of vision loss among the working population [1]
The identity of the cells involved remained ambiguous until fortuitous sections revealed the engulfment of an autophagosome-filled pericyte “ghost” (PG) by a juxtavascular microglial cell (JVM) (Figure 1A–D)
This study has provided further evidence for the involvement of excessive autophagy in the death of pericytes and vascular smooth muscle cells (SMCs) in DR

Summary

Introduction

Diabetic retinopathy (DR) continues to represent the most common complication of diabetes and a major cause of vision loss among the working population [1]. We re-analysed archival electron micrographs of retinas from diabetic dogs and human donors with diabetes and found significant evidence for the involvement of autophagy in mural cell death [6]. The current report reveals additional new evidence from human retina, that dying mural cells showing excessive autophagy can be phagocytosed by juxtavascular microglia (JVM) that have penetrated the vascular BM. Such activity by microglia has not been previously described in DR and raises questions concerning alternative fates for dying mural cells in this disease. We describe the ultrastructural features of the JVM and present evidence that they constitute an integral component of the neurovascular unit in the retina [9]

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