Early-life peripheral infections reprogram retinal microglia and aggravate neovascular age-related macular degeneration in later life
Masayuki Hata, … , Ariel M. Wilson, Przemyslaw Sapieha
Masayuki Hata, … , Ariel M. Wilson, Przemyslaw Sapieha
Published February 15, 2023
Citation Information: J Clin Invest. 2023;133(4):e159757. https://doi.org/10.1172/JCI159757.
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Research Article Ophthalmology

Early-life peripheral infections reprogram retinal microglia and aggravate neovascular age-related macular degeneration in later life

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.

Authors

Masayuki Hata, Maki Hata, Elisabeth M.M.A. Andriessen, Rachel Juneau, Frédérique Pilon, Sergio Crespo-Garcia, Roberto Diaz-Marin, Vera Guber, Francois Binet, Frédérik Fournier, Manuel Buscarlet, Caroline Grou, Virginie Calderon, Emilie Heckel, Heather J. Melichar, Jean-Sebastien Joyal, Ariel M. Wilson, Przemyslaw Sapieha

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Figure 4

CX3CR1+ myeloid cells in the retina mediate proangiogenic memory after systemic exposure to LPS.

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CX3CR1+ myeloid cells in the retina mediate proangiogenic memory after s...
(A) Time course of Cx3cr1CreER/+ and Cx3cr1CreER/+:R26iDTR/+ mice injected with 4×LPS or PBS at 7 weeks. For both Cx3cr1CreER/+ and Cx3cr1CreER/+:R26iDTR/+ mice, tamoxifen (TAM) was administered i.p. starting at 6 weeks and diphtheria toxin intravitreally (ivt) at week 11 and 12. Laser-induced CNV occurred at 11 weeks, euthanasia at week 13. (B) CNV confocal images of IB4, FITC-dextran, and IBA1 staining from Cx3cr1CreER/+ and Cx3cr1CreER/+:R26iDTR/+ mice with either 4×LPS or PBS injections. Scale bars: 20 μm. (C–F) Quantification of CNV area (C), IB4-stained laser impact area (D), FITC/IB4 ratio per laser burn (E), and number of IBA1-positive MNPs (F) on day 14; n = 24 burns (Cx3cr1CreER/+ + PBS), n = 38 burns (Cx3cr1CreER/+ + 4×LPS), n = 31 burns (Cx3cr1CreER/+:R26iDTR/+ + PBS), n = 31 burns (Cx3cr1CreER/+:R26iDTR/+ + 4×LPS). Data are presented as mean ± SEM. One-way ANOVA with Tukey’s multiple-comparison test (C–F) was used. *P < 0.05; ****P < 0.0001.