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 7

Peripheral exposure to endotoxin induces transcriptional reprogramming of myeloid cells.

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Peripheral exposure to endotoxin induces transcriptional reprogramming o...
(A) Experimental time course schematic of LPS in vivo and in vitro manipulations (B–G). C57BL/6J mice were treated with 4×LPS or PBS at 7 weeks of age and BM cells were collected at 11 weeks of age. BM cells were differentiated to BM-derived macrophages (BMDMs) with M-CSF, and BMDMs were harvested after a secondary stimulation with LPS or PBS for 4 hours. Total RNA was extracted and analyzed for gene expression by bulk RNA-seq or qPCR. (B) Volcano plot obtained from DESeq2 analysis of LPS-restimulated BMDMs from 4×LPS-prereated mice as compared with LPS-restimulated BMDMs from PBS-pretreated mice. (C) Heatmap of the top 60 most differentially expressed genes of LPS-restimulated BMDMs from 4×LPS-pretreated mice as compared with LPS-restimulated BMDMs from PBS-pretreated mice. (D) Results of GSEA of Hallmark gene sets showing those enriched in LPS-restimulated BMDMs from mice pretreated with 4×LPS as compared with LPS-restimulated BMDMs from PBS-pretreated mice (FDR < 0.1 and a nominal P value < 0.05). A positive normalized enrichment score (NES) value indicates enrichment in the 4×LPS-treated mice. (E) GSEA enrichment plots for genes related to inflammatory response and angiogenesis in LPS-restimulated BMDMs from mice pretreated with 4×LPS as compared with LPS-restimulated BMDMs from PBS-pretreated mice; n = 3. (F and G) mRNA expression in BMDMs from PBS-pretreated and 4×LPS-pretreated mice with (G) or without LPS restimulation (F): Il1b, Il6, Tnf, Tgfb1, Vegfa, Pdgfb, Postn, and Col3a1; n = 6 for all conditions. Data are presented as mean ± SEM. Comparisons between groups were analyzed using Student’s unpaired t test (F and G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.