3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina

Yehonatan Weinberger, Ivan Budnik, Yael Nisgav, Dahlia Palevski, Gil Ben-David, José A. Fernández, Shany Nivinsky Margalit, Sarina Levy-Mendelovich, Gili Kenet, Dov Weinberger, John H. Griffin, Tami Livnat

Research output: Contribution to journalArticlepeer-review

Abstract

3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision loss in age-related macular degeneration. CNV was induced by laser photocoagulation in a murine model, and 3K3A-APC was intravitreally injected. The impact of 3K3A-APC treatment on myeloid and microglia cell activation and recruitment and on NLRP3 inflammasome, IL-1β, and VEGF levels was assessed using cryosection, retinal flat-mount immunohistochemistry and vascular imaging. Additionally, we evaluated the use of fluorescein angiography as a surrogate marker for in vivo evaluation of the efficacy of 3K3A-APC treatment against leaking CNV lesions. Our results demonstrated that 3K3A-APC treatment significantly reduced the accumulation and activation of myeloid cells and microglia in the CNV area and decreased the NLRP3 and IL-1β levels at the CNV site and the surrounding retina. Furthermore, 3K3A-APC treatment resulted in leakage regression and CNV growth suppression. These findings indicate that the anti-inflammatory activities of 3K3A-APC contribute to CNV inhibition. Our study suggests the potential use of 3K3A-APC as a novel multi-target treatment for CNV.

Original languageEnglish
Article number10642
JournalInternational Journal of Molecular Sciences
Volume24
Issue number13
DOIs
StatePublished - 26 Jun 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • activated protein C
  • choroidal neovascularization
  • inflammation NLRP3
  • microglia

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