Early-life peripheral infections reprogram retinal microglia and aggravate neovascular age-related macular degeneration in later life
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
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
View: Text | PDF
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

×

Figure 1

Prior peripheral infection predisposes to pathological angiogenesis in the retina.

Options: View larger image (or click on image) Download as PowerPoint
Prior peripheral infection predisposes to pathological angiogenesis in t...
(A) Time course of Chlamydia pneumoniae (Cpn) or mock infections starting at 7 weeks. Laser-induced CNV occurred at 16 weeks, euthanasia at 18 weeks. (B) Confocal images of isolectin B4–stained (IB4-stained) laser burns with FITC-dextran–labeled CNVs. Scale bars: 20 μm. Quantification of (C) CNV area, (D) laser impact area, and (E) FITC/IB4 ratio per laser burn, all on day 14; n = 19 burns (Mock), n = 16 burns (Cpn). (F) Confocal images of mononuclear phagocytes (MNPs) stained for ionized calcium-binding adaptor molecule 1 (IBA1). Scale bars: 20 μm. (G) IBA1-positive MNP counts on day 14; n = 19 burns (Mock), n = 16 burns (Cpn). (H) Endotoxin levels (endotoxin units/mL) 5 days after infection; n = 7 per condition. Data are presented as mean ± SEM. Student’s unpaired t test (C–E, G, and H) was used. *P < 0.05; **P < 0.01; ****P < 0.0001.