IFN‐β protects from vascular leakage <i>via</i> up‐regulation of CD73

Kišš, Ján; Yegutkin, Gennady G.; Koskinen, Kaisa; Savunen, Timo; Jalkanen, Sirpa; Salmi, Marko

doi:10.1002/eji.200737793

Cited by 93 publications

(84 citation statements)

References 22 publications

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“…This barrier sealing effect is partially abolished with AMPCP, a specific inhibitor of ecto-5 0 -nucleotidase activity. This suggests a role for CD73 in mediating the inhibitory effect of IFN-b on lymphocyte transmigration through EC and is in line with exacerbated inflammation observed in CD73 deficient mice [28][29][30][31]. It is important to note that in our migration model we targeted IFN-b treatment on EC monolayer and left the lymphocytes untreated, which excludes the possibility that IFN-b treatment affected lymphocyte MMP modulation as reported earlier [27].…”

Section: Discussionsupporting

confidence: 82%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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IFN-b treatment reduces the relapse rate in MS but its mechanism of action remains incompletely understood. Our aim was to clarify the beneficial effect of IFN-b in the treatment of MS. We assessed the influence of IFN-b treatment on (i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-EC) and human astrocytes using immunofluorescence staining and flow cytometry, (ii) transmigration of CD4 1 T lymphocytes using an in vitro model of BBB and (iii) CD73 enzyme activity, i.e. ecto-5 0 -nucleotidase activity in the serum of MS patients using a radiochemical assay. IFN-b increases the expression of ecto-5 0 -nucleotidase both on BBB-EC and astrocytes. As a consequence, lymphocyte transmigration through BBB-EC is reduced. Importantly, this reduction can be reversed using a,b-methyleneadenosine-5 0 -diphosphate, a specific inhibitor of ecto-5 0 -nucleotidase. CD73 is strongly expressed in microvasculature in samples of postmortem MS brain and, moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5 0 -nucleotidase activity and skin microvascular CD73 expression after IFN-b treatment. Upregulation of ecto-5 0 -nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFN-b on MS via enhancing the endothelial barrier function.Key words: Adenosine . Blood-brain barrier . CD73 . IFN-b . MS Introduction MS is a demyelinating disease characterized by perivascular inflammatory cell infiltrates in the white matter of the CNS. MS is generally thought to be an autoimmune disease in which the immune system attack against self-antigens results in inflammation and neurological symptoms [1]. First line treatment of MS is subcutaneous or intramuscular administration of IFN-b, which leads to a reduced number of relapses and a slower disease progression [2][3][4]. The proposed beneficial effects of IFN-b include a decrease in antigen presentation, MHC class II expression, T-cell proliferation, IFN-b production, ECM degradation, and the expression of adhesion molecules [5]. Moreover, recent reports describe IFN-b as a suppressor of both myeloid [6] and Th17-cells [7]. IFN-b also reduces the number of gadolinium enhancing lesions in brain magnetic resonance imaging of MS patients [2,3,8], which is thought to reflect its ability to regulate the blood-brain barrier (BBB) function [9]. Ecto-5 0 -nucleotidase (CD73; EC 3.1.3.5) is a 70 kDa GPI-anchored glycoprotein. It is abundantly expressed on vascular endothelium and subpopulations of lymphocytes, but not on granulocytes or monocytes [10] and it also circulates in blood in a soluble 2718form [11]. Ecto-5 0 -nucleotidase activity is found on many CNS cell types such as astrocytes, oligodendrocytes, microglial cells and brain EC in many species including human, rat, mouse and bovine [12][13][14][15]. CD73 modulates the extent of immune and inflammatory responses in vitro and in vivo. These effects are mediated via its enzymatic capability ...

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Section: Discussionsupporting

confidence: 82%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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“…2015. 45: 562-573 HTS FluoroBlok TM , BD Falcon) were treated with various purinergic compounds and further assayed for transendothelial permeability by using FITC-conjugated dextran 70 kDa (Invitrogen TM , Life Technologies Europe BV), as described elsewhere [16,25]. In certain experiments, ATP, AMP, adenosine, NECA, and alloxazine (at final concentrations of 10 μM, all from Sigma) and vehicle (PBS or 0.02% DMSO, as appropriate controls) were added in serumfree conditions both to the upper and lower wells.…”

Section: In Vitro and In Vivo Permeability Assaysmentioning

confidence: 99%

“…It is synthesized both on blood ECs (BECs) and lymphatic ECs (LECs). The role of CD73 on BECs in controlling vascular permeability and leukocyte trafficking is relatively well understood [11][12][13][14][15][16][17], but the function of lymphatic CD73 remains completely enigmatic. In terms of lymphatic CD73, it is only known that the molecule is expressed on afferent, but not on efferent, LECs, that the expression is higher on LEC than BEC and also that CD73 on LECs is not involved in lymphocyte or DC homing from the periphery into the draining lymph node [18].…”

mentioning

confidence: 99%

“…Although the lymph was derived from patients with different underlying morbidities, these data thus collectively suggest that the intralymphatic lymphocytes can produce substantial levels of anti-inflammatory adenosine when they are exiting the tissues. CD73 regulates the permeability of blood vessels under inflammatory conditions [7,[11][12][13][14][15][16][17]30]. Thus, the blood vasculature of all studied organs in CD73-deficient mice has been shown to be leakier to small molecules in multiple models of ischemiareperfusion injury and LPS-induced inflammation when compared to WT mice.…”

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confidence: 99%

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Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

et al. 2014

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CD73/ecto-5 -nucleotidase is a key enzyme in the regulation of purinergic signaling and inflammatory reactions. It hydrolyzes extracellular AMP into adenosine, which dampens immune cell activation, and reduces leukocyte trafficking. By comparing CD73 expression and function in mononuclear and endothelial cells (ECs) of blood and lymph, we show that extracellular purines and CD73 activity have differential effects in these two vascular systems. We found that CD8-positive T lymphocytes and CD19-positive B lymphocytes in human lymph expressed high levels of CD73 and other purinergic enzymes and adenosine receptors. Soluble CD73 was less abundant in human lymph than in serum, whereas CD73 activity was higher in afferent lymphatic ECs than in blood ECs. Adenosine signaling improved barrier function and induced sprouting of human blood, but not lymphatic, ECs in vitro. Similarly, using CD73-deficient mice we found that CD73 controls only blood vascular permeability at selected lymphoid organs under physiological conditions. Thus, both vascular and lymphatic arms of the immune system synthesize the components of purinergic signaling system, but surprisingly they use CD73 differentially to control endothelial permeability and sprouting.Keywords: adenosine r endothelial cells r lymphatics r permeability r purinergic signaling See accompanying Commentary by Sidibé and Imhof.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPurinergic signaling plays a central role in controlling inflammation [1][2][3][4][5][6][7]. ATP and other purines are released to the cell Correspondence: Dr. Marko Salmi e-mail: marko.salmi@utu.fi exterior from intracellular pools both under physiological and pathological conditions via diverse pathways including exocytosis, specific channels, transporters, as well as cell death. On the cell surface extracellular ATP is sequentially hydrolyzed to ADP, AMP, * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 562-573 Molecular immunology 563 and adenosine through the action of specific ectonucleotidases [5]. Each of these purines can then bind to specific cell surface receptors and trigger intracellular signaling responses. Notably, ATP and ADP are proinflammatory and prothrombotic molecules, whereas adenosine usually exerts strong anti-inflammatory effects [4]. One rate-limiting enzyme in the purinergic signaling cascade is CD73/ecto-5 -nucleotidase, which converts AMP into adenosine [8,9]. CD73 is expressed on small subsets of lymphocytes, most notably on Treg cells, where it is crucial for the immunesuppressing functions [10]. CD73 is also present on endothelial cells (ECs). It is synthesized both on blood ECs (BECs) and lymphatic ECs (LECs). The role of CD73 on BECs in controlling vascular permeability and leukocyte trafficking is relatively well understood [11][12][13][14][15][16][17], but the function of lymphatic CD73 remains co...

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“…The CD73 promoter contains a cAMP response element, thus linking adenosine signalling via the A 2B R with upregulation of CD73. CD73 expression and activity is also modulated by exposure to interferon-β (IFN-β) [64]. Acute lung injury, as a systemic complication of intestinal IRI, was reduced by 90 % following IFN-β pre-treatment.…”

Section: Adenosine 1 Receptor (A 1 R)mentioning

confidence: 99%

The CD39-adenosinergic axis in the pathogenesis of renal ischemia–reperfusion injury

Roberts

Lü

Rajakumar

et al. 2012

Purinergic Signalling

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Hypoxic injury occurs when the blood supply to an organ is interrupted; subsequent reperfusion halts ongoing ischemic damage but paradoxically leads to further inflammation. Together this is termed ischemia-reperfusion injury (IRI). IRI is inherent to organ transplantation and impacts both the short-and long-term outcomes of the transplanted organ. Activation of the purinergic signalling pathway is intrinsic to the pathogenesis of, and endogenous response to IRI. Therapies targeting the purinergic pathway in IRI are an attractive avenue for the improvement of transplant outcomes and the basis of ongoing research. This review aims to examine the role of adenosine receptor signalling and the ecto-nucleotidases, CD39 and CD73, in IRI, with a particular focus on renal IRI. Ischemia-reperfusion injury (IRI) is an obligatory insult in transplantation occurring at the time of organ procurement and engraftment. Ischemia is induced when blood flow to an organ is interrupted. Re-establishment of blood flow is essential to prevent ongoing hypoxic injury but paradoxically imparts further injury, termed IRI. Warm ischemia is relatively short in brain dead donors (<30 min); however, this can be prolonged in donors following cardiac arrest (up to 90 min). Furthermore, unique to transplantation is the period of cold preservation, which slows the cellular metabolic rate in order to minimize ongoing ischemic damage but which may be prolonged (extending to hours). The clinical ramifications of IRI include systemic inflammatory effects and organ dysfunction, increasing graft immunogenicity, the risk of delayed graft function, acute rejection, and chronic allograft dysfunction. There is substantial evidence implicating purinergic signalling in both the pathogenesis of and the endogenous response to IRI, and strategies targeting various aspects of the pathway may therefore be of therapeutic potential. ATP, present in relatively high concentrations intracellularly, is extruded from injured and necrotic cells into the extracellular space or released in a more controlled manner from apoptotic cells through pannexin hemi-channels and from inflammatory cells via connexin hemi-channels [1]. Upon release, extracellular ATP acts in an autocrine or paracrine manner on specific cell-surface P2 receptors belonging to two subclasses, the G protein-coupled P2Y receptors and the ATP-gated P2X nonselective cation channels [2]. ATP Keywords

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IFN‐β protects from vascular leakage via up‐regulation of CD73

Cited by 93 publications

References 22 publications

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

The CD39-adenosinergic axis in the pathogenesis of renal ischemia–reperfusion injury

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