PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration

Anitha Krishnan*, Victor G. Sendra, Diyan Patel, Amit Lad, Michelle K. Greene, Peter Smyth, Samantha A. Gallaher, Úna M. Herron, Christopher J. Scott, Mohamed Genead, Michael Tolentino

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
25 Downloads (Pure)

Abstract

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1β, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Original languageEnglish
Article number1237016
Number of pages18
JournalFrontiers in Immunology
Volume14
DOIs
Publication statusPublished - 16 Nov 2023

Bibliographical note

Funding Information:
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Publisher Copyright:
Copyright © 2023 Krishnan, Sendra, Patel, Lad, Greene, Smyth, Gallaher, Herron, Scott, Genead and Tolentino.

Keywords

  • AMD (age-related macular degeneration)
  • macrophages
  • nanoparticles
  • polysia mimetics
  • Siglec

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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