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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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 8

Prior peripheral exposure to endotoxins shifts myeloid cells toward proangiogenic polarization.

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Prior peripheral exposure to endotoxins shifts myeloid cells toward proa...
(A) Representative flow cytometry plots of M1- and M2-like macrophages in BMDMs of PBS-pretreated mice and 4×LPS-pretreated mice. (B and C) Quantification of M2-like macrophages (F4/80+CD11b+CD11c−CD206+) (B) and M1-like macrophages (F4/80+CD11b+CD11c+CD206−) (C) in BMDMs of PBS-pretreated mice and 4×LPS-prereated mice (n = 6). (D) Schematic representation of ex vivo choroid sprouting assay cocultured with BM monocytes (BM-Mo). C57BL/6J mice were treated with 4×LPS or PBS at 7 weeks of age and were subjected to laser burns at 11 weeks. BM cells were collected 3 days after laser burn and BM-Mo were isolated using immunomagnetic negative selection. Choroid pieces (RPE-choroid-sclera from peripheral retina of 5-week-old C57BL/6J mice) were seeded into 24-well plates containing Matrigel and cocultured with BM-Mo using Transwell inserts. (E) Representative images of choroid explants at 2 and 3 days of coculture with BM-Mo from PBS-pretreated and 4×LPS-pretreated mice, and without BM-Mo. (F and G) Quantitation of sprouting area at 2 (F) and 3 days (G) of coculture with BM-Mo from each group when compared with no BM-Mo. At 2 days, n = 19 (No BM-Mo), 14 (PBS BM-Mo), n = 15 (4×LPS BM-Mo). At 3 days, n = 16 (No BM-Mo), 14 (PBS BM-Mo), n = 14 (4×LPS BM-Mo). Data are presented as mean ± SEM. Comparisons between groups were analyzed using Student’s unpaired t test (B and C) or 1-way ANOVA with Tukey’s multiple-comparison test (F and G). *P < 0.05; **P < 0.01.