Mast cell hyperactivity underpins the development of oxygen-induced retinopathy
Kenshiro Matsuda, … , Akane Tanaka, Hiroshi Matsuda
Kenshiro Matsuda, … , Akane Tanaka, Hiroshi Matsuda
Published October 9, 2017
Citation Information: J Clin Invest. 2017;127(11):3987-4000. https://doi.org/10.1172/JCI89893.
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Research Article Angiogenesis Inflammation Article has an altmetric score of 6

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.

Authors

Kenshiro Matsuda, Noriko Okamoto, Masatoshi Kondo, Peter D. Arkwright, Kaoru Karasawa, Saori Ishizaka, Shinichi Yokota, Akira Matsuda, Kyungsook Jung, Kumiko Oida, Yosuke Amagai, Hyosun Jang, Eiichiro Noda, Ryota Kakinuma, Koujirou Yasui, Uiko Kaku, Yasuo Mori, Nobuyuki Onai, Toshiaki Ohteki, Akane Tanaka, Hiroshi Matsuda

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Figure 6

Tryptase directly induced the expression of angiogenic factors in retinal endothelial cells.

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Tryptase directly induced the expression of angiogenic factors in retina...
(A) Mcp1 mRNA expression was significantly increased in OIR mice. This was suppressed by administration of cromolyn, but administration of PBS alone did not have any effect. Other angiogenic factors, Vegf and Fgf, were upregulated in OIR mice and decreased by cromolyn treatment. On P11 and P12, WT mice were injected with PBS or cromolyn, and eyes were collected at 6 hours after the second administration on P12. n = 8 in each group. **P < 0.01 versus PBS-injected mice, Dunnett’s test. (B) Addition of recombinant mMCP6 into the culture of primary retinal endothelial cells induced Mcp1, Vegf, Fgf, and Hgf gene expression. n = 8 in each group. *P < 0.05; **P < 0.01 versus vehicle treatment, Mann-Whitney U test. (C) Schematic of Mcp1 gene–silencing experiments. Intravitreal injection of MCP1 siRNA effectively suppressed retinal MCP1 expression. n = 8 in each group. **P < 0.01 versus control RNA-injected mice, Mann-Whitney U test. (D) Abnormal angiogenesis, following relative hypoxia, was suppressed by the specific inhibition of MCP1 in the retina. Neovascularization area (%) was quantified in whole-mount specimens. n = 8 in each group. **P < 0.01 versus PBS-injected mice, Mann-Whitney U test. (E) Relative hypoxia induced the formation of new abnormal blood vessels (white areas) in WT mice (n = 14), but not in CCR2-deficent mice (n = 8). **P < 0.01 versus WT mice, Mann-Whitney U test. (F) Addition of recombinant mMCP6 into the culture of primary retinal endothelial cells induced typical tube formation. The effect of mMCP6 was suppressed by addition of anti-MCP1 mAbs. n = 4 in each group. *P < 0.05 versus rat isotype mAb, Dunnett’s test. (G) Addition of recombinant mouse MCP1 (10 ng/ml) into the culture of primary retinal endothelial cells induced typical vascular tube formation. n = 4 in each group. **P < 0.01 versus vehicle control, Mann-Whitney U test. Scale bars: 500 μm (D, E); 100 μm (F, G). All results are shown as mean ± SEM of values determined from 3 to 4 independent experiments.