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Journal of Neuroinflammation

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Open Access 01-12-2023 | Fingolimod | Research

Assessing the role of T cells in response to retinal injury to uncover new therapeutic targets for the treatment of retinal degeneration

Authors: Federica M. Conedera, Judith M. Runnels, Jens V. Stein, Clemens Alt, Volker Enzmann, Charles P. Lin

Published in: Journal of Neuroinflammation | Issue 1/2023

Abstract

Background

Retinal degeneration is a disease affecting the eye, which is an immune-privileged site because of its anatomical and physiological properties. Alterations in retinal homeostasis—because of injury, disease, or aging—initiate inflammatory cascades, where peripheral leukocytes (PL) infiltrate the parenchyma, leading to retinal degeneration. So far, research on PL's role in retinal degeneration was limited to observing a few cell types at specific times or sectioning the tissue. This restricted our understanding of immune cell interactions and response duration.

Methods

In vivo microscopy in preclinical mouse models can overcome these limitations enabling the spatio-temporal characterization of PL dynamics. Through in vivo imaging, we assessed structural and fluorescence changes in response to a focal injury at a defined location over time. We also utilized minimally invasive techniques, pharmacological interventions, and knockout (KO) mice to determine the role of PL in local inflammation. Furthermore, we investigated PL abundance and localization during retinal degeneration in human eyes by histological analysis to assess to which extent our preclinical study translates to human retinal degeneration.

Results

We demonstrate that PL, especially T cells, play a detrimental role during retinal injury response. In mice, we observed the recruitment of helper and cytotoxic T cells in the parenchyma post-injury, and T cells also resided in the macula and peripheral retina in pathological conditions in humans. Additionally, we found that the pharmacological PL reduction and genetic depletion of T-cells reduced injured areas in murine retinas and rescued the blood–retina barrier (BRB) integrity. Both conditions promoted morphological changes of Cx3cr1⁺ cells, including microglial cells, toward an amoeboid phenotype during injury response. Interestingly, selective depletion of CD8⁺ T cells accelerated recovery of the BRB compared to broader depletions. After anti-CD8 treatment, the retinal function improved, concomitant to a beneficial immune response.

Conclusions

Our data provide novel insights into the adaptive immune response to retinal injury in mice and human retinal degeneration. Such information is fundamental to understanding retinal disorders and developing therapeutics to modulate immune responses to retinal degeneration safely.

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Title: Assessing the role of T cells in response to retinal injury to uncover new therapeutic targets for the treatment of retinal degeneration
Authors: Federica M. Conedera
Judith M. Runnels
Jens V. Stein
Clemens Alt
Volker Enzmann
Charles P. Lin
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Fingolimod
Published in: Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02867-x

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Assessing the role of T cells in response to retinal injury to uncover new therapeutic targets for the treatment of retinal degeneration

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway