ORIGINAL RESEARCH article
Front. Immunol.
Sec. Systems Immunology
Granzyme B from Mast Cells Contributes to Choroidal Neovascularization in a Model of Wet Age-Related Macular Degeneration
Provisionally accepted
Manjosh Uppal
Amir Hosseini
Khola Bilal
Nielan Tan
Zhengyuan AiWania KhanIsa SamadGurmohit Gill
Hyung-Suk YooHarshini ChakravarthyChuan-Hui KuoJeanne Xi
David J Granville
Joanne Matsubara*- University of British Columbia, Vancouver, Canada
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Purpose: Wet age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV), yet current anti-VEGF therapies are ineffective in many patients. This study investigates the role of mast cell–derived granzyme B (GzmB), a serine protease responsible for the abnormal cleavage of the extracellular matrix in the outer retina. Methods: Human and mouse choroidal tissues were analyzed for mast cell distribution, GzmB expression, and age-related changes. An ex vivo choroidal sprouting assay (CSA) was used to evaluate the effects of mast cell degranulation and/or stabilization, and the pharmacologic inhibition of GzmB, using tissues from wild-type and GzmB knockout (KO) mice. Results: Aging increased mast cell accumulation and degranulation in both the human and mouse choroid, leading to elevated GzmB. GzmB KO mice exhibited reduced choroidal sprouting, and exogenous GzmB promoted angiogenesis. Both GzmB inhibition and mast cell stabilization suppressed angiogenic events, confirming GzmB's role in mast cell-driven angiogenesis. Conclusions: GzmB is a key mediator of mast cell-induced CNV. Targeting GzmB, either directly or through mast cell stabilization, offers a promising strategy for reducing angiogenesis in a condition such as wet AMD.
Keywords: Angiogenesis, Bruch's membrane, Choroidal sprouting, degranulation, Extracellular Matrix, Outer retina, Retinal Pigment Epithelium, serine protease
Received: 22 Sep 2025; Accepted: 03 Feb 2026.
Copyright: © 2026 Uppal, Hosseini, Bilal, Tan, Ai, Khan, Samad, Gill, Yoo, Chakravarthy, Kuo, Xi, Granville and Matsubara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Joanne Matsubara
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