Early-life peripheral infections reprogram retinal microglia and aggravate neovascular age-related macular
Masayuki Hata1,2, Maki Hata1, Elisabeth Mma Andriessen3
1Department of Ophthalmology.
Abstract:
Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic association between genes of innate immunity and AMD, genome-to-phenome relationships are low, suggesting a critical contribution of environmental triggers of disease. Possible insight comes from the observation that a past history of infection with pathogens such as Chlamydia pneumoniae, or other systemic inflammation, can predispose to nvAMD in later life. Using a mouse model of nvAMD with prior C. pneumoniae infection, endotoxin exposure, and genetic ablation of distinct immune cell populations, we demonstrated that peripheral infections elicited epigenetic reprogramming that led to a persistent memory state in retinal CX3CR1+ mononuclear phagocytes (MNPs). The immune imprinting persisted long after the initial inflammation had subsided and ultimately exacerbated choroidal neovascularization in a model of nvAMD. Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identified activating transcription factor 3 (ATF3) as a central mediator of retina-resident MNP reprogramming following peripheral inflammation. ATF3 polarized MNPs toward a reparative phenotype biased toward production of proangiogenic factors in response to subsequent injury. Therefore, a past history of bacterial endotoxin-induced inflammation can lead to immunological reprograming within CNS-resident MNPs and aggravate pathological angiogenesis in the aging retina.
Insights
Past infections can cause lasting immune changes in the eye, increasing the risk of age-related macular degeneration (AMD). This immune memory exacerbates pathological neovascularization (nvAMD) later in life.
Area of Science:
- Immunology
- Ophthalmology
- Genetics
Background:
- Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly.
- While genetic factors are known, environmental triggers are crucial for AMD development.
- Past infections, like Chlamydia pneumoniae, may predispose individuals to pathological neovascularization in AMD (nvAMD).
Purpose of the Study:
- To investigate how peripheral infections influence the development of nvAMD.
- To understand the role of epigenetic reprogramming in retinal immune cells following inflammation.
- To identify molecular mechanisms linking past infections to exacerbated nvAMD.
Main Methods:
- Utilized a mouse model of nvAMD with prior C. pneumoniae infection and endotoxin exposure.
- Employed genetic ablation of specific immune cell populations.
- Conducted single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on retinal mononuclear phagocytes (MNPs).
Main Results:
- Peripheral infections induced epigenetic reprogramming and a persistent memory state in retinal CX3CR1+ MNPs.
- This immune imprinting, even after inflammation subsided, exacerbated choroidal neovascularization in the nvAMD model.
- Activating transcription factor 3 (ATF3) was identified as a key mediator, polarizing MNPs toward a proangiogenic phenotype.
Conclusions:
- Past bacterial endotoxin-induced inflammation can reprogram central nervous system-resident MNPs.
- This reprogramming leads to immunological memory that aggravates pathological angiogenesis in the aging retina.
- Targeting ATF3 may offer therapeutic strategies for nvAMD.
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