Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis.
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.
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Hirokazu
H
Sato
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Masaaki
M
Higashiyama
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Hideaki
H
Hozumi
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Shingo
S
Sato
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Hirotaka
H
Furuhashi
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Takeshi
T
Takajo
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Koji
K
Maruta
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Yuichi
Y
Yasutake
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Kazuyuki
K
Narimatsu
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Kenichi
K
Yoshikawa
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Chie
C
Kurihara
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Yoshikiyo
Y
Okada
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Chikako
C
Watanabe
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Shunsuke
S
Komoto
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Kengo
K
Tomita
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and.
Shigeaki
S
Nagao
National Defense Medical College, Saitama, Japan.
Soichiro
S
Miura
Department of Internal Medicine, National Defense Medical College, Saitama, Japan; and ryota@ndmc.ac.jp.
Ryota
R
Hokari
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000098853:Podoplanin
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008562:Membrane Glycoproteins; D010975:Platelet Aggregation Inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3; C117468:PDPN protein, human; D000098853:Podoplanin; C581309:FLT4 protein, human
inflammatory bowel disease; lymphangiogenesis; lymphatic vessels; platelet; podoplanin