Macrophages and Neutrophils Infiltrating into the Liver Are Responsible for Tissue Factor Expression in a Rabbit Model of Acute Obstructive Cholangitis

Higure, Aiichiro; Okamoto, Kohji; Hirata, Keiji; Todoroki, Hidekazu; Nagafuchi, Yukihisa; Takeda, Satoru; Katoh, Hidenori; Itoh, Hideaki; Ohsato, Keiichi; Nakamura, Shin

doi:10.1055/s-0038-1650368

Cited by 50 publications

(36 citation statements)

References 20 publications

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“…Our study opposes the concept created in early 1970s that granulocytes synthesize TF in vivo [19][20][21] and in vitro. [22][23][24] It has been shown that TF promoter in neutrophils contains cytosine-phosphateguanosine CpG islands, which are not heavily methylated.…”

Section: Discussioncontrasting

confidence: 88%

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

Egorina

Sovershaev

Olsen

et al. 2008

Blood

108

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Unlike unanimous opinion on tissue factor (TF) expression in monocytes, the quest for TF presence in granulocytes has been going on for decades. To study the cell origin and track the blood-borne TF, we assessed TF activity and protein levels, knocked-down endogenous TF expression with small interfering RNA (siRNA), and overexpressed TF-yellow fluorescent protein (TF-YFP) fusion in immunologically isolated human monocytes and granulocytes. Monocytes and, to a much lesser extent, granulocytes isolated from lipopolysaccharide (LPS)/ phorbol 12-myristate-13-acetate (PMA)-stimulated whole blood contained active TF antigen. However, only monocytes possessed significant TF activity and protein levels when stimulated with LPS/PMA in suspension. Reintroduction of TF-silenced monocytes to whole blood led to a profound reduction of LPS/PMA-stimulated TF activity in both mononuclear cell (MNC) and granulocyte fractions. No reduction in TF activity in MNC and granulocyte fractions was observed when TFsilenced granulocytes were reintroduced to whole blood. As shown by immunoblotting, flow cytometry, and confocal microscopy, granulocytes became positive for TF-YFP when isolated from whole blood reconstituted with TF-YFP-expressing monocytes. Together, we pinpoint monocytes as a major source of TF and provide solid experimental evidence for a direct transfer of TF protein from the monocytes to granulocytes in the blood. IntroductionThe source of tissue factor (TF) among circulating blood leukocytes still remains a mystery that is bolstered by several conflicting reports. 1-7 TF is a 45-kDa membrane glycoprotein that binds to factor F VII (FVII)/FVIIa with high affinity. 8 The formation of TF-FVIIa complexes triggers the coagulation cascade by activating both factors IX and X, which leads to thrombin generation and stimulates platelet activation and fibrin deposition. [9][10][11] Under physiologic conditions, TF is absent in the cells and tissues located on the interface with circulating blood. It is constitutively expressed in vascular cell types that have no direct contact with blood, such as adventitial fibroblasts, pericytes, and smooth muscle cells. 12 This mode of expression provides a haemostatic protection should vascular injury occur. In 1989, Drake et al created a concept of TF as being a "haemostatic envelope ready to activate coagulation when vascular integrity is disrupted." 13 Although studies demonstrating the presence of TF on circulating blood cells began in the early 1970s, the question of which blood cell type expresses TF is still a matter of considerable discussion. 14,15 To date, neutrophils, eosinophils, platelets, and even lymphocytes were shown to be positive for TF protein under diverse conditions. [2][3][4][5][6][7] In our present study, we studied TF procoagulant activity and antigen in highly pure resting and stimulated monocytes and granulocytes under conditions of whole blood and plating. Having used small interfering RNA (siRNA)-mediated knockdown of endogenous TF expression in freshly isolated ...

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Section: Discussioncontrasting

confidence: 88%

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

Egorina

Sovershaev

Olsen

et al. 2008

Blood

108

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“…Whether intravascular cells other than monocytes and endothelial cells express TF has been the subject of debate for over 10 years. Expression of TF on neutrophils has been reported by some authors (102,125), but denied by others (221). This controversy may be explained by the possibility that neutrophils can take up TF from other blood cells (113).…”

Section: Tf On Intravascular Cellsmentioning

confidence: 99%

New Fundamentals in Hemostasis

Versteeg

Heemskerk

Levi

et al. 2013

Physiological Reviews

908

831

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Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surrounding tissue. The first important component that contributes to hemostasis is the coagulation system, while the second important component starts with platelet activation, which not only contributes to the hemostatic plug, but also accelerates the coagulation system. Eventually, coagulation and platelet activation are switched off by blood-borne inhibitors and proteolytic feedback loops. This review summarizes new concepts of activation of proteases that regulate coagulation and anticoagulation, to give rise to transient thrombin generation and fibrin clot formation. It further speculates on the (patho)physiological roles of intra-and extravascular receptors that operate in response to these proteases. Furthermore, this review provides a new framework for understanding how signaling and adhesive interactions between endothelial cells, leukocytes, and platelets can regulate thrombus formation and modulate the coagulation process. Now that the key molecular players of coagulation and platelet activation have become clear, and their complex interactions with the vessel wall have been mapped out, we can also better speculate on the causes of thrombosis-related angiopathies.

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“…1, A and B) is in vivo evidence that neutrophils express TF in inflammation by immune stimuli as in the case of inflammation by nonspecific stimuli (Higure et al, 1996;Todoroki et al, 1998Todoroki et al, , 2000. Giesen et al (1999) have found TF-bearing neutrophils in ex vivo study using pig arterial media and collagen-coated glass slides exposed to flowing native human blood, while de novo TF production in the neutrophils was not shown.…”

Section: Discussionmentioning

confidence: 99%

“…Taking together the cases of AR and LPS-induced inflammation (Higure et al, 1996;Todoroki et al, 1998Todoroki et al, , 2000, TF expression and presumably elastase fibrinolysis are likely to be general functions of neutrophils in inflammation and may be associated with inflammationinduced hypercoagulability and subsequent bleeding tendency, such as disseminated intravascular coagulation.…”

Section: Discussionmentioning

confidence: 99%

“…We showed previously that infiltrated macrophages induced clotting by expressing TF on the cell membrane, leading to formation of induration (Imamura et al, 1993), a skin lesion characteristic of DTH reaction and associated with fibrin deposition (Colvin and Dvorak, 1975). With regard to inflammation by nonspecific stimuli, we found TF expression on accumulated neutrophils and fibrin clot in liver sinusoid of rabbits and monkeys that had received intravenous injection of bacterial lipopolysaccharides (LPS) (Higure et al, 1996;Todoroki et al, 1998Todoroki et al, , 2000, suggesting participation of neutrophils in Immunohistochemical staining of Arthus reaction (AR) skin tissues using antibodies against either tissue factor (TF) or elastase. A, TF staining of 6-hour AR skin.…”

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confidence: 96%

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New Functions of Neutrophils in the Arthus Reaction: Expression of Tissue Factor, the Clotting Initiator, and Fibrinolysis by Elastase

Imamura

Kaneda

Nakamura

2002

Laboratory Investigation

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SUMMARY:The products of the blood clotting reaction, eg, thrombin and fibrinopeptides, have various proinflammatory activities and are suggested to modulate inflammation. The macrophage expression of tissue factor (TF), the clotting initiator, has been shown to cause clotting in the site of the delayed-type hypersensitivity reaction, a cellular immune response. However, the mechanism of the clotting induction in humoral immune response has been insufficiently studied. Therefore, the Arthus reaction, a model of immune-complex diseases, was produced in monkey skin that was examined for TF expression and fibrin deposition. TF antigen was positive on most of polymorphonuclear leukocytes, which were the main leukocytes in the lesions and were identified as neutrophils with an anti-neutrophil-elastase mAb. TF mRNA was detected in neutrophils by in situ hybridization using TF RNA probes, indicating de novo TF synthesis by the leukocytes. Specific binding of activated factor VII onto TF-positive neutrophils suggested the activity of neutrophil TF to trigger the cascade reaction of clotting. The number of TF-positive neutrophils were correlated in time with the intensity and extent of fibrin deposition that was visualized with an mAb specific for fibrin and peaked in 24 hours. Interestingly, the fibrin deposit was partially positive for an mAb specific for neutrophil elastase-digested fibrin. These results show in vivo evidence of a close relationship between neutrophils and both clotting and fibrinolysis in the Arthus reaction and may suggest that these neutrophil functions contribute to the pathogenesis of this hypersensitivity inflammation. (Lab Invest 2002, 82:1287-1295.

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Macrophages and Neutrophils Infiltrating into the Liver Are Responsible for Tissue Factor Expression in a Rabbit Model of Acute Obstructive Cholangitis

Cited by 50 publications

References 20 publications

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

New Fundamentals in Hemostasis

New Functions of Neutrophils in the Arthus Reaction: Expression of Tissue Factor, the Clotting Initiator, and Fibrinolysis by Elastase

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