Absence of the Endothelial Oxidase AOC3 Leads to Abnormal Leukocyte Traffic In Vivo

Stolen, Craig M.; Marttila-Ichihara, Fumiko; Koskinen, Kaisa; Yegutkin, Gennady G.; Turja, Raisa; Bono, Petri; Skurnik, Mikael; Hänninen, Arno; Jalkanen, Sirpa; Salmi, Marko

doi:10.1016/j.immuni.2004.12.006

Cited by 114 publications

(153 citation statements)

References 42 publications

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…Co-cultures were incubated in culture medium for 3 days and pulsed with 3 H-thymidine (1 mCi [0.037 MBq] per well) for the final 6 h. Cells were harvested using semi-automated plate harvester (Tomtech MACH III) and counted with the 1450 Microbeta counter (Wallac). The Ab titers against OVA were determined by ELISA as described [31]. The phenotype analyses were carried out as explained above.…”

Section: Immunizationsmentioning

confidence: 99%

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

et al. 2009

Self Cite

View full text Add to dashboard Cite

Clever-1/Stabilin-1 is a scavenger receptor present on lymphatic and sinusoidal endothelium as well as on a subset of type II macrophages. It is also induced on vasculature at sites of inflammation. However, its in vivo function has remained practically unknown and this work addresses those unknown aspects. We demonstrate using in vivo models that Clever-1/Stabilin-1 mediates migration of T and B lymphocytes to the draining lymph nodes in vivo and identify the adhesive epitope of the Clever-1/Stabilin-1 molecule responsible for the interaction between lymphocytes and lymphatic endothelium. Moreover, we demonstrate that Ab blocking of Clever-1/Stabilin-1 efficiently inhibits peritonitis in mice by decreasing the entrance of granulocytes by 50%, while migration of monocytes and lymphocytes into the inflamed peritoneum is prevented almost completely. Despite efficient anti-inflammatory activity the Ab therapy does not dramatically dampen immune responses against the bacterial and foreign protein Ag tested and bacterial clearance. These results indicate that anti-Clever-1/Stabilin-1 treatment can target two different arms of the vasculature -traffic via lymphatics and inflamed blood vessels. IntroductionImmune cell trafficking between blood and lymphoid organs is an essential element in the proper functioning of the immune system. The mechanisms mediating lymphocyte entrance from the blood into the lymphoid organs and leukocyte trafficking to sites of inflammation are well known [1][2][3]. In contrast, mechanisms involved in lymphocyte migration from the periphery via the afferent lymphatics into the draining lymph nodes and their exit from the lymph nodes are poorly known. Besides lymphocytes, many tumors also use lymphatics for dissemination to distant sites of the body [4]. Eur. J. Immunol. 2009. 39: 3477-3487 DOI 10.1002 Innate immunity 3477Clever-1/Stabilin-1, also known as Feel-1, is a multifunctional molecule possessing scavenging ability on a subset of type II macrophages [5,6]. It is also present both on afferent and efferent lymphatic endothelial cells and sinusoidal endothelial cells in the liver and spleen [7][8][9][10]. In man, it is brightly expressed on high endothelial venules (HEV), which are the specific vessels within organized lymphatic tissues mediating lymphocyte entrance into the tissues, and on sinusoidal macrophages. Moreover, at sites of inflammation its expression is induced in flat-walled vessels. On lymphatic vasculature it is able to bind lymphocytes and certain tumor cells and on inflamed blood vessel endothelium it can mediate adhesion of lymphocytes, granulocytes and monocytes [8,11]. In vitro analyses have indicated it to be important in the transmigration step during the leukocyte extravasation process [12].Clever-1/Stabilin-1 is involved in two intracellular trafficking pathways, namely in receptor mediated endocytosis and recycling as well as in shuttling between endosomal compartment and trans-Golgi network. These complex mechanisms require interactions with several molecules ...

show abstract

Section: Immunizationsmentioning

confidence: 99%

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…VAP-1-dependent leukocyte trafficking has been shown so far only in three inflammatory conditions (peritonitis, arthritis and mucosal vaccination) using VAP-1 deficient mice in vivo [21][22][23]. The role of VAP-1 in two mechanistically different and clinically relevant models, IRI and remote organ injury caused by systemic inflammation, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, the antibodies do not inhibit the enzymatic activity of VAP-1 and the SSAO inhibitors do not affect the surface epitopes of the molecule seen by the neutralizing antibodies [19,20]. Thus, VAP-1 is envisaged to have both enzyme-activity-dependent and enzyme-activity-independent functions in supporting leukocyte-endothelial interactions.VAP-1-dependent leukocyte trafficking has been shown so far only in three inflammatory conditions (peritonitis, arthritis and mucosal vaccination) using VAP-1 deficient mice in vivo [21][22][23]. The role of VAP-1 in two mechanistically different and clinically relevant models, IRI and remote organ injury caused by systemic inflammation, remains unknown.…”

mentioning

confidence: 99%

Ischemia‐reperfusion injury is attenuated in VAP‐1‐deficient mice and by VAP‐1 inhibitors

et al. 2008

Self Cite

View full text Add to dashboard Cite

Neutrophils mediate the damage caused by ischemia-reperfusion both at the site of primary injury and in remote organs. Vascular adhesion protein-1 (VAP-1) is an ectoenzyme expressed on endothelial cells and it has been shown to regulate leukocyte extravasation. Here we show for the first time using VAP-1-deficient mice that VAP-1 plays a significant role in the intestinal damage and acute lung injury after ischemiareperfusion. Separate inhibition of VAP-1 by small molecule enzyme inhibitors and a function-blocking monoclonal antibody in WT mice revealed that the catalytic activity of VAP-1 is responsible for its pro-inflammatory action. The use of transgenic humanized VAP-1 mice also showed that the enzyme inhibitors alleviate both the ischemia-reperfusion injury in the gut and neutrophil accumulation in the lungs. These data thus indicate that VAP-1 regulates the inflammatory response in ischemia-reperfusion injury and suggest that blockade of VAP-1 may have therapeutic value.Key words: Adhesion molecules . Inflammation . Ischemia-reperfusion injury IntroductionInteraction between leukocytes and endothelium, which allows leukocyte extravasation to the tissues, forms an essential part of host defense. This interaction is mediated via adhesion molecules expressed on the surface of leukocytes and endothelium [1]. Although indispensable for normal immune response, increased leukocyte trafficking to the tissues has deleterious consequences in certain diseases [2][3][4][5].Diseases caused by ischemia are the leading cause of death in the developed countries. Since ischemia causes tissue necrosis, its treatment consists of restoration of blood flow to the ischemic tissue. Although reperfusion is necessary to prevent further damage to the ischemic tissue, it triggers an inflammatory response that aggravates ischemia-induced tissue damage [6]. Therefore, ischemia-reperfusion (IR) injury (IRI) complicates treatment of many potentially fatal diseases. A hallmark of IRI is sequestration of neutrophils in the reperfused tissues. Excessive neutrophil extravasation is to a large extent a consequence of increased expression and/or avidity of adhesion molecules on the surface of endothelial cells and neutrophils [1,7].Inflammatory response to IR can cause damage not only in reperfused tissues but also in remote organs. Pro-inflammatory cytokines released at the site of reperfusion enter circulation and activate endothelium and circulating leukocytes in multiple vascular beds [2,6]. Although systemic inflammatory response may lead to development of dysfunction anywhere in the body, lungs are the most frequently injured organ [8,9]. Indirect acute lung injury (ALI) can appear alone or as a part of multiple organ dysfunction syndrome, in which it is a strong independent risk factor for death [10]. Since increased leukocyte trafficking plays a major role in both IR and remote organ injury, identification of the molecules involved in neutrophil infiltration is of paramount importance for the development of an effective treatment. Va...

show abstract

“…To generate mTIEhVAP-1-transgenic/VAP-1-knockout (VAP KO+TG) mice, mTIEhVAP-1 line E35 mice expressing human VAP-1 on the vasculature [38] were crossed to VAP-1-knockout mice that were previously created by using conventional gene targeting techniques to replace the mouse VAP-1 gene with a nonfunctional mutant allele [11]. The mTIEhVAP-1-transgenic, mouse VAP-1 mutant allele and endogenous mouse VAP-1 allele were all identified by PCR screening of purified genomic DNA with specific primers and verified immunohistochemically with human and mouse VAP-1 antibodies [38].…”

Section: In Vivo Peritonitis Model For Transmigrationmentioning

confidence: 99%

“…In addition to this, VAP-1 knockout mouse models have shown that lack of the protein leads to increased rolling velocity and a decreased rate of leukocyte transmigration [11]. Recent work has also demonstrated that VAP-1 functions as a regulator of neutrophil transmigration [12].…”

Section: Introductionmentioning

confidence: 98%

Function-blocking antibodies to human vascular adhesion protein-1: A potential anti-inflammatory therapy

et al. 2005

Self Cite

View full text Add to dashboard Cite

Human vascular adhesion protein-1 (VAP-1) is a homodimeric 170-kDa sialoglycoprotein that is expressed on the surface of endothelial cells and functions as a semicarbazidesensitiveamineoxidase and as an adhesion molecule. Blockade of VAP-1has been shown to reduce leukocyte adhesion and transmigration in in vivo and in vitro models, suggesting that VAP-1 is a potential target for anti-inflammatory therapy. In this study we have constructed mouse-human chimeric antibodies by genetic engineering in order to circumvent the potential problems involved in using murine antibodies in man. Our chimeric anti-VAP-1 antibodies, which were designed to lack Fc-dependent effector functions, bound specifically to cell surface-expressed recombinant human VAP-1 and recognized VAP-1 in different cell types in tonsil. Furthermore, the chimeric antibodies prevented leukocyte adhesion and transmigration in vitro and in vivo. Hence, these chimeric antibodies have the potential to be used as a new anti-inflammatory therapy.

show abstract

Absence of the Endothelial Oxidase AOC3 Leads to Abnormal Leukocyte Traffic In Vivo

Cited by 114 publications

References 42 publications

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

Ischemia‐reperfusion injury is attenuated in VAP‐1‐deficient mice and by VAP‐1 inhibitors

Function-blocking antibodies to human vascular adhesion protein-1: A potential anti-inflammatory therapy

Contact Info

Product

Resources

About