TY - JOUR
T1 - Monocytic thrombomodulin promotes cell adhesion through interacting with its ligand, Lewis y
AU - Lin, Wei Ling
AU - Chen, Chia Chi
AU - Shi, Guey Yueh
AU - Ma, Chih Yuan
AU - Chang, Chuan Fa
AU - Wu, Hua Lin
N1 - Funding Information:
This work was supported by Ministry of Science and Technology (Taipei, Taiwan, MOST-102-2320-B-006-039-MY2) and a grant from the Top-Notch Project of the National Cheng Kung University (Taiwan).
Publisher Copyright:
© 2017 Australasian Society for Immunology Inc.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - The leukocyte adhesion cascade involves multiple events that efficiently localize circulating leukocytes into the injured sites to mediate inflammatory responses. From rolling to firm adhesion, the interactions between adhesion molecules have pivotal roles in increasing the avidity of leukocytes to endothelial cells. Thrombomodulin (TM), an essential anticoagulant protein in the vasculature, is also expressed on leukocytes. We previously demonstrated that Lewis y (Le y), a specific ligand of TM, is upregulated in inflamed endothelium and is involved in leukocyte adhesion. The current study aimed to investigate whether leukocyte-expressed TM promotes cell adhesion by interacting with Le y. Using human monocytic THP-1 cells as an in vitro cell model, we showed that TM increases THP-1 cell adhesion to inflamed endothelium as well as to Le y -immobilized surface. When THP-1 adhered to activated endothelium and Le y -immobilized surface, the TM distribution became polarized. Addition of soluble Le y to a suspension of THP-1 cells with TM expression triggered an increase in the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which enabled THP-1 to adhere firmly to intercellular adhesion molecule (ICAM)-1 by activating β 2 integrins. In vivo, macrophage infiltration and neointima formation following arterial ligation-induced vascular injury were higher in wild-type TM (TM flox/flox) than in myeloid-specific TM-deficient (LysMcre/TM flox/flox) mice. Taken together, these results suggest a novel function for TM as an adhesion molecule in monocytes, where it enhances cell adhesion by binding Le y, leading to β 2 integrin activation via p38 MAPK.
AB - The leukocyte adhesion cascade involves multiple events that efficiently localize circulating leukocytes into the injured sites to mediate inflammatory responses. From rolling to firm adhesion, the interactions between adhesion molecules have pivotal roles in increasing the avidity of leukocytes to endothelial cells. Thrombomodulin (TM), an essential anticoagulant protein in the vasculature, is also expressed on leukocytes. We previously demonstrated that Lewis y (Le y), a specific ligand of TM, is upregulated in inflamed endothelium and is involved in leukocyte adhesion. The current study aimed to investigate whether leukocyte-expressed TM promotes cell adhesion by interacting with Le y. Using human monocytic THP-1 cells as an in vitro cell model, we showed that TM increases THP-1 cell adhesion to inflamed endothelium as well as to Le y -immobilized surface. When THP-1 adhered to activated endothelium and Le y -immobilized surface, the TM distribution became polarized. Addition of soluble Le y to a suspension of THP-1 cells with TM expression triggered an increase in the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which enabled THP-1 to adhere firmly to intercellular adhesion molecule (ICAM)-1 by activating β 2 integrins. In vivo, macrophage infiltration and neointima formation following arterial ligation-induced vascular injury were higher in wild-type TM (TM flox/flox) than in myeloid-specific TM-deficient (LysMcre/TM flox/flox) mice. Taken together, these results suggest a novel function for TM as an adhesion molecule in monocytes, where it enhances cell adhesion by binding Le y, leading to β 2 integrin activation via p38 MAPK.
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U2 - 10.1038/icb.2016.110
DO - 10.1038/icb.2016.110
M3 - Article
C2 - 27808085
AN - SCOPUS:85000786787
SN - 0818-9641
VL - 95
SP - 372
EP - 379
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 4
ER -