Interferon Regulatory Factor 3 Deficiency Induces Age-Related Alterations of the Retina in Young and Old Mice

Zhang, Xi; Zhu, Jianwei; Chen, Xian-Jun; Zhang, Jieqiong; Li, Xue; Lu, Luo; Huang, Huang; Liu, Wenyi; Zhou, Xinyuan; Yan, Jun; Lin, Sen; Ye, Jian

doi:10.3389/fncel.2019.00272

Cited by 9 publications

(5 citation statements)

References 52 publications

(64 reference statements)

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“…However, Cx3cr1 tm1Zm mice on the BALB/cJ background show complete nuclei loss at 4 months of age [426]. Cxcr5 tm1Lipp causes late onset PR degeneration with 20% loss of ONL thickness at 17 months of age and RPE disorganization [427], whereas ablation of Irf3 and Igfbp3 showed mild PR degeneration at 2-4 months of age, about 10-14% [428,429]. Ccl2 and Ccr2 mutations also led to PR degeneration and fundus lesions, ONL loss in some areas and development of neovascular lesions, resembling phenotypes of AMD [430].…”

Section: Category 11: Immune Responsementioning

confidence: 99%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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Section: Category 11: Immune Responsementioning

confidence: 99%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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“…Aberrant activity of each corresponding transcription factor has been associated with cancer development or worsened prognosis 79,[105][106][107][108][109][110][111][112][113][114][115] . Some of these, such as E2F3 116 and IRF3 117 , have been associated with aging-related diseases, whereas a connection for others has yet to be discovered.…”

Section: Resultsmentioning

confidence: 99%

Development of a novel epigenetic clock resistant to changes in immune cell composition

Verdin

Tomusiak

Floro

et al. 2023

Preprint

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Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age. We found that human naive CD8+ T cells, which decrease during aging, exhibit an epigenetic age 15–20 years younger than effector memory CD8+ T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created a new clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock showed a robust predicted epigenetic age increase in a model of replicative senescence in vitro and age reversal during OSKM-mediated reprogramming.

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“…IRF8 was recently reported to play a critical role in retinal microglial homeostasis in steady state and microglial reactivation in laser injury, which negatively impacts choroidal neovascularization (CNV), leading to reduced CNV size [ 42 ]. IRF3 is critical in regulating retinal senescence during aging, as old IRF3 -/- mice showed retinal abnormalities in retinal structure and function compared with the young IRF3 -/- mice [ 43 ]. IRF5 mediates LPS-induced microglia activation and neuroinflammation in the CNS [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Interferon Regulatory Factor 1 in Regulating Microglial Activation and Retinal Inflammation

Yang

Diaz

2022

IJMS

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Microglia are resident immune cells in the central nervous system (CNS). Microglial activation plays a prominent role in neuroinflammation and CNS diseases. However, the underlying mechanisms of microglial activation are not well understood. Here, we report that the transcription factor interferon regulatory factor 1 (IRF1) plays critical roles in microglial activation and retinal inflammation by regulating pro- and anti-inflammatory gene expression. IRF1 expression was upregulated in activated retinal microglia compared to those at the steady state. IRF1 knockout (KO) in BV2 microglia cells (BV2ΔIRF1) created by CRISPR/Cas9 genome-editing technique causes decreased microglia proliferation, migration, and phagocytosis. IRF1-KO decreased pro-inflammatory M1 marker gene expression induced by lipopolysaccharides (LPS), such as IL-6, COX-2, and CCL5, but increased anti-inflammatory M2 marker gene expression by IL-4/13, such as Arg-1, CD206, and TGF-β. Compared to the wild-type cells, microglial-conditioned media (MCM) of activated BV2ΔIRF1 cell cultures reduced toxicity or death to several retinal cells, including mouse cone photoreceptor-like 661 W cells, rat retinal neuron precursor R28 cells, and human ARPE-19 cells. IRF1 knockdown by siRNA alleviated microglial activation and retinal inflammation induced by LPS in mice. Together, the findings suggest that IRF1 plays a vital role in regulating microglial activation and retinal inflammation and, therefore, may be targeted for treating inflammatory and degenerative retinal diseases.

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Interferon Regulatory Factor 3 Deficiency Induces Age-Related Alterations of the Retina in Young and Old Mice

Cited by 9 publications

References 52 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Development of a novel epigenetic clock resistant to changes in immune cell composition

The Role of Interferon Regulatory Factor 1 in Regulating Microglial Activation and Retinal Inflammation

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