Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Schlecht, Anja; Thien, Adrian; Wolf, Julian; Prinz, Gabriele; Agostini, Hansjürgen; Schlunck, Günther; Wieghofer, Peter; Boneva, Stefaniya; Lange, Clemens

doi:10.3390/ijms222413318

Cited by 9 publications

(7 citation statements)

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“… 10 Accumulating evidence suggests that senescent macrophage/microglia, which might actually polarize toward the M2 phenotype, play a key role in abnormal angiogenesis. 11 , 12 However, the detailed mechanisms that regulate macrophage/microglia phenotypes and functions, particularly in aging-associated eye diseases, remain largely unclear.…”

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confidence: 99%

Therapeutic Benefit of Melatonin in Choroidal Neovascularization During Aging Through the Regulation of Senescent Macrophage/Microglia Polarization

Cui

Tang

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose This study aimed to investigate the age-dependent anti-angiogenic capability of melatonin in choroidal neovascularization (CNV) and to explore the underlying molecular mechanisms. Methods In the present study, a laser-induced CNV model was established in both young (three months of age) and old (18 months of age) mice, and the size of CNV lesions and vascular leakage was detected by morphological and imaging examination. Next, Western blot and immunostaining were used to observe the levels of M2 markers, senescence-related markers, and molecules involved in IL-10/STAT3 pathway. Additionally, colivelin was used to study the effect of IL-10/STAT3 pathway activation on the expression of M2 markers and senescence-related markers by Western blot and immunostaining. Finally, the effects of colivelin on melatonin-induced reduction of CNV size and vascular leakage in mice at different ages were assessed using morphological and imaging examination. Results Our results revealed that aging promoted M2 macrophage/microglia polarization, and aggravated CNV and vascular leakage. Melatonin significantly inhibited the M2 polarization of senescent macrophage/microglia and reduced the CNV area and vascular leakage. Moreover, melatonin markedly suppressed IL-10/STAT3 pathway activation in the macrophage/microglia of old mice, and STAT3 activator colivelin reversed the suppressive effect of melatonin on M2 polarization of senescent macrophage/microglia and laser-induced CNV in old mice. Conclusions Our data demonstrated that melatonin significantly prevented the M2 polarization of senescent macrophage/microglia by inhibiting the IL-10/STAT3 pathway, and eventually attenuated senescence-associated CNV. These findings suggested that melatonin could serve as a promising therapeutic agent to treat CNV and other age-related ocular diseases.

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mentioning

confidence: 99%

Therapeutic Benefit of Melatonin in Choroidal Neovascularization During Aging Through the Regulation of Senescent Macrophage/Microglia Polarization

Cui

Tang

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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“…Finally, for the comparison between human and murine microglia, mice aged at least 2 years were investigated resembling the average age of the patients that were included in this study. Since the age has a considerable influence on the expression profile of retinal microglia (18), discrepancies must be taken into account when investigating younger mice. A strength of this study is the use of fresh tissue, which was processed instantly after enucleation, allowing to preserve the RNA of sorted cells within four hours after surgery, which is significantly faster compared to other studies using post-mortem tissue with a time from death to preservation of 8 up to 17 h (36,38).…”

Section: Discussionmentioning

confidence: 99%

“…The transcriptional profile of murine retinal microglia previously published by our group (18) was re-analyzed and compared to data from human retinal microglia acquired in this study. In brief, immediately after enucleation, eyes were dissected in icecold PBS to isolate the retinae.…”

Section: Micementioning

confidence: 99%

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In-Depth Molecular Profiling Specifies Human Retinal Microglia Identity

et al. 2022

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Microglia are the tissue-resident macrophages of the retina and brain, being critically involved in organ development, tissue homeostasis, and response to cellular damage. Until now, little is known about the molecular signature of human retinal microglia and how it differs from the one of brain microglia and peripheral monocytes. In addition, it is not yet clear to what extent murine retinal microglia resemble those of humans, which represents an important prerequisite for translational research. The present study applies fluorescence-activated cell sorting to isolate human retinal microglia from enucleated eyes and compares their transcriptional profile with the one of whole retinal tissue, human brain microglia as well as classical, intermediate and non-classical monocytes. Finally, human retinal microglia are compared to murine retinal microglia, isolated from Cx3cr1GFP/+ mice. Whereas human retinal microglia exhibited a high grade of similarity in comparison to their counterparts in the brain, several enriched genes were identified in retinal microglia when compared to whole retinal tissue, as well as classical, intermediate, and non-classical monocytes. In relation to whole retina sequencing, several risk genes associated with age-related macular degeneration (AMD) and diabetic retinopathy (DR) were preferentially expressed in retinal microglia, indicating their potential pathophysiological involvement. Although a high degree of similarity was observed between human and murine retinal microglia, several species-specific genes were identified, which should be kept in mind when employing mouse models to investigate retinal microglia biology. In summary, this study provides detailed insights into the molecular profile of human retinal microglia, identifies a plethora of tissue-specific and species-specific genes in comparison to human brain microglia and murine retinal microglia, and thus highlights the significance of retinal microglia in human retinal diseases and for translational research approaches.

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“…In addition to the disease-associated induction of endothelial LRG1 expression, myeloid cells have also been found to express LRG1 in choroidal neovascularization. A recent study exploring the transcriptional profiling of immunosenescence in myeloid cells during the development of CNV showed that aged senescent myeloid cells of CNV-induced animals exhibited an upregulated angiogenic transcriptional profile with significantly elevated Lrg1 and Arg1 expression compared to young cells ( 115 ). This is the first study to provide evidence of upregulated Lrg1 expression in cells other than the endothelium contributing to choroidal neovascularization.…”

Section: Lrg1 and Vascular Pathology Of The Eyementioning

confidence: 99%

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Dritsoula,

Camilli,

Moss

et al. 2024

Front. Cardiovasc. Med.

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The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.

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Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

Cited by 9 publications

References 73 publications

Therapeutic Benefit of Melatonin in Choroidal Neovascularization During Aging Through the Regulation of Senescent Macrophage/Microglia Polarization

Therapeutic Benefit of Melatonin in Choroidal Neovascularization During Aging Through the Regulation of Senescent Macrophage/Microglia Polarization

In-Depth Molecular Profiling Specifies Human Retinal Microglia Identity

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

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