Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis

淋巴管新生 淋巴管 淋巴系统 淋巴管内皮 结肠炎 血小板 炎症 炎症性肠病 医学 平足蛋白 血管内皮生长因子C 免疫学 癌症研究 病理 血管内皮生长因子 血管内皮生长因子A 内科学 癌症 转移 血管内皮生长因子受体 疾病
作者
Hírokazu Sato,Masaaki Higashiyama,Hideaki Hozumi,Shingo Sato,Hirotaka Furuhashi,Takeshi Takajo,Koji Maruta,Yuichi Yasutake,Kazuyuki Narimatsu,Kenichi Yoshikawa,Chie Kurihara,Yoshikiyo Okada,Chikako Watanabe,Shunsuke Komoto,Kengo Tomita,Shigeaki Nagao,Soichiro Miura,Ryota Hokari
出处
期刊:American Journal of Physiology-gastrointestinal and Liver Physiology [American Physiological Society]
卷期号:311 (2): G276-G285 被引量:20
标识
DOI:10.1152/ajpgi.00455.2015
摘要

Lymphatic failure is a histopathological feature of inflammatory bowel disease (IBD). Recent studies show that interaction between platelets and podoplanin on lymphatic endothelial cells (LECs) suppresses lymphangiogenesis. We aimed to investigate the role of platelets in the inflammatory process of colitis, which is likely to be through modulation of lymphangiogenesis. Lymphangiogenesis in colonic mucosal specimens from patients with IBD was investigated by studying mRNA expression of lymphangiogenic factors and histologically by examining lymphatic vessel (LV) densities. Involvement of lymphangiogenesis in intestinal inflammation was studied by administering VEGF-receptor 3 (VEGF-R3) inhibitors to the mouse model of colitis using dextran sulfate sodium and evaluating platelet migration to LVs. The inhibitory effect of platelets on lymphangiogenesis was investigated in vivo by administering antiplatelet antibody to the colitis mouse model and in vitro by coculturing platelets with lymphatic endothelial cells. Although mRNA expressions of lymphangiogenic factors such as VEGF-R3 and podoplanin were significantly increased in the inflamed mucosa of patients with IBD compared with those with quiescent mucosa, there was no difference in LV density between them. In the colitis model, VEGF-R3 inhibition resulted in aggravated colitis, decreased lymphatic density, and increased platelet migration to LVs. Administration of an antiplatelet antibody increased LV densities and significantly ameliorated colitis. Coculture with platelets inhibited proliferation of LECs in vitro. Our data suggest that despite elevated lymphangiogenic factors during colonic inflammation, platelet migration to LVs resulted in suppressed lymphangiogenesis, leading to aggravation of colitis by blocking the clearance of inflammatory cells. Modulating the interaction between platelets and LVs could be a new therapeutic means for treating IBD.
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