Matsuda Kenshiro, Okamoto Noriko, Kondo Masatoshi, Arkwright Peter D, Karasawa Kaoru, Ishizaka Saori, Yokota Shinichi, Matsuda Akira, Jung Kyungsook, Oida Kumiko, Amagai Yosuke, Jang Hyosun, Noda Eiichiro, Kakinuma Ryota, Yasui Koujirou, Kaku Uiko, Mori Yasuo, Onai Nobuyuki, Ohteki Toshiaki, Tanaka Akane, Matsuda Hiroshi
Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan.
Laboratory of Veterinary Molecular Pathology and Therapeutics, and Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
J Clin Invest. 2017 Nov 1;127(11):3987-4000. doi: 10.1172/JCI89893. Epub 2017 Oct 9.
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.
传统观点认为，肥大细胞在抵御蠕虫感染以及诱导过敏性疾病方面发挥着重要作用；然而，最近的研究表明，这些细胞也参与了新血管生成过程，而新血管生成对于组织重塑、慢性炎症和癌症发生至关重要。在此，我们证明了在氧诱导性视网膜病变（OIR）小鼠模型中，肥大细胞对于发芽血管生成至关重要。尽管缺乏肥大细胞的小鼠品系在缺氧后未表现出视网膜新生血管形成，但在输注肥大细胞或注射肥大细胞类胰蛋白酶（MCT）后，这些小鼠发生了OIR。相对缺氧通过瞬时受体电位锚蛋白1刺激肥大细胞脱颗粒。随后MCT的激增刺激视网膜内皮细胞产生单核细胞趋化蛋白-1（MCP1）和血管生成因子，从而导致发芽血管生成。肥大细胞稳定剂以及特定的类胰蛋白酶和MCP1抑制剂可预防野生型小鼠发生OIR。患有早期早产儿视网膜病变的早产儿血浆MCT水平明显高于年龄匹配的无病婴儿，这表明肥大细胞与人类疾病有关。总之，这些结果表明，作为预防由新血管生成引起的眼部疾病及后续失明的潜在选择，应进一步探索抑制肥大细胞活性的疗法。
