# The IL-6 Induced Retinal Iron Sequestration Response

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $389,152

## Abstract

PROJECT SUMMARY
Iron plays a critical role in both the healthy and diseased retina. The long term goals of the
proposed studies are to understand how inflammation associated with retinal disease
promotes iron dysregulation, and discover how to protect against retinal iron toxicity. Iron is
necessary in the retina for mitochondrial energy production, membrane synthesis and the
visual cycle, but becomes a central producer of oxidative stress when improperly regulated.
Iron toxicity is evident in retinal disease as follows: 1) Iron causes rapid retinal degeneration
following entry into the eye carried by an intraocular foreign body. 2) Human AMD retinas have
more iron than age-matched controls, suggesting that iron overload may play a role in AMD
pathogenesis. 3) Consistent with this hypothesis, in the inherited disease aceruloplasminemia,
loss of the ferroxidase ceruloplasmin (Cp) results in retinal iron accumulation and early onset
macular degeneration. 4) Mice with knockout for Cp and its homolog hephaestin (Heph) have
an age-dependent retinal iron overload and degeneration sharing features of AMD, including
complement activation and subretinal neovascularization (which causes wet AMD). Recent
evidence from non-ocular cells indicates that interleukin 6 (IL-6) can trigger a “cellular iron
sequestration response” to prevent microbes from accessing the iron they need for growth and
replication. This, combined with the finding of elevated intraocular and serum IL-6 levels in
AMD, suggest that IL-6 may promote retinal iron overload in AMD. Experiments proposed
herein will utilize human iPSC-RPE cell culture, mouse models, and post mortem human tissue
to define the IL-6 retinal iron sequestration response. An inhibitor of the IL-6 trans-signaling
pathway will be tested. Following activation or inhibition of IL-6 pathways, changes in the levels
of iron and its transporters will be assessed. These changes will be correlated with those in
AMD versus normal post mortem retinas. It is expected that these studies will lead to
development of novel anti-AMD approaches that diminish inflammation-induced iron
accumulation.

## Key facts

- **NIH application ID:** 10416008
- **Project number:** 5R01EY028916-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOSHUA L DUNAIEF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,152
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416008

## Citation

> US National Institutes of Health, RePORTER application 10416008, The IL-6 Induced Retinal Iron Sequestration Response (5R01EY028916-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10416008. Licensed CC0.

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