Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Ophthalmology Article has an altmetric score of 6

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

  • Text
  • PDF
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 7

Peripheral exposure to endotoxin induces transcriptional reprogramming of myeloid cells.

Options: View larger image (or click on image) Download as PowerPoint
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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 8 X users
30 readers on Mendeley
See more details