Mast cell hyperactivity underpins the development of oxygen-induced retinopathy

Abstract

Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.

Validation of antibodies for the specific detection of human TRPA1

“…We found no evidence of expression of TRPA1 in CD45+ CD117+ human lung mast cells. Previous work has suggested expression of TRPA1 by other mast cells 20,21 , including those from other species. We note that this work 20,21 was completed using NB110-40763 which is not specific for TRPA1.…”

VEGF‐Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy

“…The oxygen‐induced retinopathy (OIR) mouse model is the most widely used animal model to study ischemic neovascular retinopathies including retinopathy of prematurity and late neovascular proliferative diabetic retinopathy (Smith et al ; Stahl et al ). As in human ischemic retinopathy patients, retinal function is markedly impaired in OIR mice (Stahl et al ; Dorfman et al ; Vessey et al ; Ridano et al ; Matsuda et al ). Moreover these mice also exhibit reduced numbers of dopaminergic amacrine cells (Spix et al ) and delayed intermediate vascular plexus formation (Ritter et al ; Spix et al ).…”

New Insights Into Immunological Therapy for Retinal Disorders

“…The administration of a neutralizing antibody against MIP-1β inhibits physiological angiogenesis (113); therefore, we believe that MIP-1β has the potential to be a useful inflammatory biomarker of ROP progression or recurrence rather than a therapeutic target molecule. Moreover, Matsuda et al reported that mast cell tryptase (MCT) released from mast cells is involved in angiogenesis in ROP (114). They demonstrated that MCT promotes angiogenesis by inducing the production of MCP-1 and other angiogenic factors from endothelial cells (114).…”

“…Moreover, Matsuda et al reported that mast cell tryptase (MCT) released from mast cells is involved in angiogenesis in ROP (114). They demonstrated that MCT promotes angiogenesis by inducing the production of MCP-1 and other angiogenic factors from endothelial cells (114). On account that the serum MCT level is elevated in infants with ROP, MCT also has the potential to be a useful biomarker of ROP progression.…”