Conditional Müller Cell Ablation Leads to Retinal Iron Accumulation

Abstract

PurposeRetinal iron accumulation is observed in a wide range of retinal degenerative diseases, including AMD. Previous work suggests that Müller glial cells may be important mediators of retinal iron transport, distribution, and regulation. A transgenic model of Müller cell loss recently demonstrated that primary Müller cell ablation leads to blood–retinal barrier leakage and photoreceptor degeneration, and it recapitulates clinical features observed in macular telangiectasia type 2 (MacTel2), a rare human disease that features Müller cell loss. We used this mouse model to determine the effect of Müller cell loss on retinal iron homeostasis.MethodsChanges in total retinal iron levels after Müller cell ablation were measured using inductively coupled plasma mass spectrometry. Corresponding changes in the expression of iron flux and iron storage proteins were determined using quantitative PCR, Western analysis, and immunohistochemistry.ResultsMüller cell loss led to blood–retinal barrier breakdown and increased iron levels throughout the neurosensory retina. There were corresponding changes in mRNA and/or protein levels of ferritin, transferrin receptor, ferroportin, Zip8, and Zip14. There were also increased iron levels within the RPE of retinal sections from a patient with MacTel2 and both RPE and neurosensory retina of a patient with diabetic retinopathy, which, like MacTel2, causes retinal vascular leakage.ConclusionThis study shows that Müller cells and the blood–retinal barrier play pivotal roles in the regulation of retinal iron homeostasis. The retinal iron accumulation resulting from blood–retinal barrier dysfunction may contribute to retinal degeneration in this model and in diseases such as MacTel2 and diabetic retinopathy.

Single-Cell RNA Sequencing in Human Retinal Degeneration Reveals Distinct Glial Cell Populations

“…Reactive astrogliosis is marked by astrocyte proliferation and migration, which may have led to an increased number of peripherally localized astrocytes available for recovery in the AIR donor, consistent with recent single-cell RNA sequencing studies characterizing microglial proliferation in response to retinal damage in mice [38]. Collectively, the gliotic injury response induced by Müller cells and astrocytes has many neuroprotective benefits, yet chronic gliotic activation can further injure retinal neurons and disrupt the blood-retinal barrier, leading to worsening vision [39,40]. In the setting of chronic retinal injury, interventions that modulate gliotic activation may optimize preservation of remaining retinal function [41].…”

Iron is neurotoxic in retinal detachment and transferrin confers neuroprotection

“…After detachment, acute RPE alteration ( 6 ) may favor free iron entry. Similarly, a breakdown of the inner blood-retinal barrier in an animal model of type 2 macular telangiectasia, a rare human disease, led to iron accumulation in the retina and PR degeneration ( 19 ). However, iron accumulation was also shown in retinal dystrophies, especially in PRs, without obvious barrier breakdowns ( 20 ), suggesting that other mechanisms contribute to iron increases.…”

Roles of Drug Transporters in Blood-Retinal Barrier

“…Loss of Müller cells was reported to break down the BRB and increase iron levels throughout the neurosensory retina of mice (Baumann et al 2017). Müller cell loss or dysfunction often occurs in patients with macular telangiectasia type 2 (MacTel2) and diabetic retinopathy, which may explain the clinical findings that a patient with MacTel2 and a patient with diabetic retinopathy had the increased iron levels in RPE or neurosensory retina (Baumann et al 2017). TGF-β was reported to impair function of BRB via simulating metalloproteinases (MMPs) from Müller cells, later degrading tight junction protein occludin (Behzadian et al 2001).…”