LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin

Kawamoto, Eiji; Okamoto, Takayuki; Takagi, Yoshimi; Honda, Goichi; Suzuki, Koji; Imai, Hiroshi; Shimaoka, Motomu

doi:10.1016/j.bbrc.2016.04.007

Cited by 18 publications

(14 citation statements)

References 26 publications

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“…Our results that β 1 integrin mediates TM-enhanced VSMCs migration and the fact that TM-enhanced FAK activation is dependent on the CS moiety again point to the activation of β 1 integrin-FAK in mediating TM-enhanced VSMCs migration. In this context, the serine/threonine-rich domain of TM was shown to interact with β 2 integrin expressed on peripheral blood mononuclear cells in vitro [ 42 ]. Further study is required to unravel how the CS moiety of TM interacts with integrin-FAK pathway as we were unable to detect the binding complex between TM and β 1 integrin (CP Pai and MJ Jiang, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells

Pai

Yan

et al. 2018

J Biomed Sci

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BackgroundThrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis. Under inflammatory states, TM expression is drastically reduced in ECs while vascular smooth muscle cells (VSMCs) show a robust expression of TM. The functional role of TM in VSMCs remains elusive.MethodsWe examined the role of TM in VSMCs activities in human aortic VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB). Using rat embryonic aorta-derived A7r5 VSMCs which do not express TM, the role of the chondroitin sulfate (CS) moiety of TM in VSMCs was delineated with cells expressing wild-type TM and the CS-devoid TM mutant.ResultsExpression of TM enhanced cell migration and adhesion/spreading onto type I collagen, but had no effect on cell proliferation. Knocking down TM with short hairpin RNA reduced PDGF-stimulated adhesion and migration of human aortic VSMCs. In A7r5 cells, TM-mediated cell adhesion was eradicated by pretreatment with chondroitinase ABC which degrades CS moiety. Furthermore, the TM mutant (TMS490, 492A) devoid of CS moiety failed to increase cell adhesion, spreading or migration. Wild-type TM, but not TMS490, 492A, increased focal adhesion kinase (FAK) activation during cell adhesion, and TM-enhanced cell migration was abolished by a function-blocking anti-integrin β1 antibody.ConclusionChondroitin sulfate modification is required for TM-mediated activation of β1-integrin and FAK, thereby enhancing adhesion and migration activity of VSMCs.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0415-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells

Pai

Yan

et al. 2018

J Biomed Sci

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“…Furthermore, APC suppresses lipopolysaccharide (LPS)-induced increases in the pulmonary accumulation of leukocytes, as well as vascular permeability [ 57 ]. Moreover, APC, TM and EPCR directly bind to leukocyte integrins, an interaction that may regulate leukocyte adhesion to inflamed endothelium [ 58 , 59 , 60 ]. Therefore, the protein C pathway plays a pivotal role in the negative regulation of both blood coagulation and inflammation.…”

Section: The Crosstalk Between Inflammation and Blood Coagulationmentioning

confidence: 99%

The Role of Gap Junction-Mediated Endothelial Cell–Cell Interaction in the Crosstalk between Inflammation and Blood Coagulation

Okamoto

Suzuki

2017

IJMS

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Endothelial cells (ECs) play a pivotal role in the crosstalk between blood coagulation and inflammation. Endothelial cellular dysfunction underlies the development of vascular inflammatory diseases. Recent studies have revealed that aberrant gap junctions (GJs) and connexin (Cx) hemichannels participate in the progression of cardiovascular diseases such as cardiac infarction, hypertension and atherosclerosis. ECs can communicate with adjacent ECs, vascular smooth muscle cells, leukocytes and platelets via GJs and Cx channels. ECs dynamically regulate the expression of numerous Cxs, as well as GJ functionality, in the context of inflammation. Alterations to either result in various side effects across a wide range of vascular functions. Here, we review the roles of endothelial GJs and Cx channels in vascular inflammation, blood coagulation and leukocyte adhesion. In addition, we discuss the relevant molecular mechanisms that endothelial GJs and Cx channels regulate, both the endothelial functions and mechanical properties of ECs. A better understanding of these processes promises the possibility of pharmacological treatments for vascular pathogenesis.

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“…It is thought that rsTM suppresses leukocyte adhesion and migration by blocking LPS, HMGB1, and extracellular histones, thereby leading to amelioration of inflammation and organ injury [8,44]. Moreover, we and other groups have shown that rsTM inhibits the adhesion that occurs between leukocytes and endothelial cells by directly blocking integrin-integrin ligand interactions [45][46][47]. Unlike these mechanisms by which rsTM suppresses leukocyte adhesion, the results of the current study provide the first evidence that an rsTM-mediated reduction of endothelial cellular stiffness contributes to the suppression of monocyte adhesion to inflamed endothelial cells.…”

Section: Discussionmentioning

confidence: 92%

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening

Okamoto

Kawamoto

Usuda

et al. 2020

Cells

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Endothelial cellular stiffening has been observed not only in inflamed cultured endothelial cells but also in the endothelium of atherosclerotic regions, which is an underlying cause of monocyte adhesion and accumulation. Although recombinant soluble thrombomodulin (rsTM) has been reported to suppress the inflammatory response of endothelial cells, its role in regulating endothelial cellular stiffness remains unclear. The purpose of this study was to investigate the impact of anticoagulant rsTM on lipopolysaccharide (LPS)-induced endothelial cellular stiffening. We show that LPS increases endothelial cellular stiffness by using atomic force microscopy and that rsTM reduces LPS-induced cellular stiffening not only through the attenuation of actin fiber and focal adhesion formation but also via the improvement of gap junction functionality. Moreover, post-administration of rsTM, after LPS stimulation, attenuated LPS-induced cellular stiffening. We also found that endothelial cells regulate leukocyte adhesion in a substrate- and cellular stiffness-dependent manner. Our result show that LPS-induced cellular stiffening enhances monocytic THP-1 cell line adhesion, whereas rsTM suppresses THP-1 cell adhesion to inflamed endothelial cells by reducing cellular stiffness. Endothelial cells increase cellular stiffness in reaction to inflammation, thereby promoting monocyte adhesion. Treatment of rsTM reduced LPS-induced cellular stiffening and suppressed monocyte adhesion in a cellular stiffness-dependent manner.

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LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin

Cited by 18 publications

References 26 publications

The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells

The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells

The Role of Gap Junction-Mediated Endothelial Cell–Cell Interaction in the Crosstalk between Inflammation and Blood Coagulation

Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening

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