Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis

American Journal of Physiology - Gastrointestinal and Liver Physiology - Tập 311 Số 2 - Trang G276-G285 - 2016
Hirokazu Sato1, Masaaki Higashiyama1, Hideaki Hozumi1, Shingo Sato1, Hirotaka Furuhashi1, Takeshi Takajo1, Koji Maruta1, Yuichi Yasutake1, Kazuyuki Narimatsu1, Kenichi Yoshikawa1, Chie Kurihara1, Yoshikiyo Okada1, Chikako Watanabe1, Shunsuke Komoto1, Kengo Tomita1, Shigeaki Nagao1, Soichiro Miura2, Ryota Hokari1
1Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and
2National Defense Medical College. Saitama, Japan

Tóm tắt

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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Tài liệu tham khảo

10.1111/j.1749-6632.2010.05757.x

10.1016/j.crohns.2013.04.005

10.1038/nm.2545

10.1172/JCI200522037

10.1038/nature10908

10.1016/j.devcel.2010.01.009

Bollman JL, 1948, J Lab Clin Med, 33, 1349

10.1111/j.1365-2249.2012.04602.x

10.1161/CIRCRESAHA.110.218073

10.1089/lrb.2010.0004

10.1186/1479-5876-11-207

10.1172/JCI20465

10.1172/JCI72189

10.1053/j.gastro.2006.03.054

10.1172/JCI36077

10.1002/ibd.21150

Geleff S, 2003, Virchows Arch, 442, 231, 10.1007/s00428-002-0744-4

10.1159/000198452

10.1080/10739680701703551

Hokari R, 2001, J Leukoc Biol, 70, 896, 10.1189/jlb.70.6.896

10.1158/0008-5472.CAN-07-2366

10.1007/s00018-011-0848-6

Jurisic G, 2013, Inflamm Bowel Dis, 19, 1983

10.1371/journal.pone.0032084

10.1007/s00418-008-0525-5

10.1136/gut.30.7.983

Matts SG, 1961, Q J Med, 30, 393

10.1074/jbc.M111.329987

10.1007/s00428-007-0540-2

10.1111/j.1365-2036.2011.04759.x

10.1097/MIB.0b013e3182971cec

10.1016/j.prostaglandins.2014.11.001

10.3748/wjg.v20.i29.9699

10.1002/path.2935

10.1016/j.cell.2010.01.045

10.1097/MOG.0b013e3283476e8f

10.1002/ibd.20896

10.1073/pnas.1310479110

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Thông tin xuất bản

American Journal of Physiology - Gastrointestinal and Liver Physiology

Tập 311 Số 2

G276-G285

Thông tin tác giả