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 3

Prior systemic exposure to endotoxin mitigates retinal neuroinflammation.

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Prior systemic exposure to endotoxin mitigates retinal neuroinflammation...
(A) Time course of peripheral LPS stimuli, where C57BL/6J mice received injections of LPS once (1×LPS), 4 daily injections of LPS (4×LPS), or 4 daily injections of PBS (PBS) at 7 weeks. Laser-induced CNV occurred at 11 weeks and euthanasia 3 days or 2 weeks later. Naive mice received PBS injections but no laser burns. (B–H) mRNA expression in retina/RPE-choroid-sclera complexes 3 days after CNV induction (PBS, 1×LPS, and 4×LPS) of Il1b (B), Tnf (C), Il6 (D), Vegfa (E), Tgfb1 (F), Tlr4 (G), and Aif1 (H): n = 6 (naive), n = 7 (PBS), n = 7 (1×LPS), n = 7 (4×LPS). (I and J) mRNA expression in RPE-choroid-sclera complexes 3 days after CNV induction (PBS, 1×LPS, and 4×LPS) or without CNV induction (naive) relative to PBS of (I) Tnf and (J) Vegfa: n = 3 (naive), n = 8 (PBS), n = 8 (1×LPS), n = 9 (4×LPS). (K and L) Flow cytometric analyses of whole retinas and RPE-choroid-sclera complexes 3 days after CNV induction. Plots and percentage of viable mononuclear phagocytes (MNPs) (K) and CX3CR1+ MNPs (L) in naive (n = 9), PBS (n = 6), 1×LPS (n = 6), and 4×LPS (n = 6) groups. (M) Confocal images of IBA1-stained MNPs on day 14 of PBS-, 1×LPS-, and 4×LPS-treated groups. Scale bars: 20 μm. (N) Number of IBA1-positive MNPs around laser impact area on day 14; n = 40 burns (PBS), n = 29 burns (1×LPS), n = 23 burns (4×LPS). Data are presented as mean ± SEM. One-way ANOVA with Tukey’s multiple-comparison test (B–L and N) was used. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.