# Mechanisms of toll-like receptor-mediated neurotoxicity in the ischemic retina

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $383,750

## Abstract

PROJECT SUMMARY
Ischemic injury to retinal tissue is a clinical condition that frequently leads to visual impairments and blindness,
affecting patients' quality of life and functional status. But a more rigorous understanding of the mechanisms of
ischemia-induced retinal injury will be required if new therapies for the management of retinal disease are to be
developed. Previously, we demonstrated the deleterious role of toll-like receptor 4 (Tlr4) signaling in retinal
inflammation and damage triggered by ischemic conditions. Since Tlr4 signaling consists of two distinct
signaling cascades, Myd88- and Trif-dependent, we individually evaluated the role of these cascades in
ischemic retinae. Available evidence appears to indicate that the effects mediated by Trif and Myd88 signaling
in ischemic retinal tissue are retina-specific and asymmetric. Whereas inactivation of either Trif or Myd88
resulted in significantly reduced inflammation in ischemic retinal tissue, ischemic retinae of Myd88-deficient
animals demonstrated significantly higher levels of damage than ischemic retinae of Trif-deficient animals. We
also noted that ischemia-induced Trif signaling directly facilitates necrotic retinal ganglion cell (RGC) death.
Furthermore, we demonstrated that RGC necrosis, which exacerbates retinal injury by promoting more
inflammation, can be regulated in some cases (termed “necroptosis”). Since Trif signaling can mediate cell
necroptosis, we hypothesize in Aim 1 that Trif signaling mediates ischemia-induced retinal damage by
promoting RGC necroptosis. In addition, Trif-dependent signaling differs from the Myd88 signaling cascade in
its ability to activate type I interferon (IFN) signaling. It was previously shown that Trif, via its activation of IFN,
activates caspase-11 (Casp11), which can in turn mediate cell death both directly and indirectly (via NLRP3
inflammasome activity and interleukin-1b [Il1b] release). In light of our finding of high levels of Casp11 and
inflammasome activity in ischemic RGCs, we hypothesize in Aim 2 that ischemia-induced Trif signaling
mediates Casp11 activation, which in turn mediates RGC death both directly and indirectly (via elevated
inflammatory responses). Finally, since Müller glia (MG) activity is associated with neuroprotection in nearly
every pathological condition in the retina, we hypothesize in Aim 3 that ischemia-induced, MG-specific, Tlr4-
dependent neuroprotective activity prevails over neurotoxic activity to facilitate survival of ischemic RGCs. If
the proposed hypotheses are found to be correct, we will be able to explain the asymmetric roles of Trif and
Myd88 in ischemic retinal tissue: while Myd88 regulates glial toxicity (astrocytes and microglia) and
neuroprotection (MG) in ischemic retinae, Trif activates both aforementioned phenomena while also directly
mediating RGC death, thus promoting more significant retinal damage than Myd88. To evaluate our
hypotheses, we will use animal models and employ a wide r...

## Key facts

- **NIH application ID:** 9878856
- **Project number:** 5R01EY027311-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Dmitry V Ivanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878856

## Citation

> US National Institutes of Health, RePORTER application 9878856, Mechanisms of toll-like receptor-mediated neurotoxicity in the ischemic retina (5R01EY027311-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878856. Licensed CC0.

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