Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells

Alfano, Massimo; Mariani, Samanta A.; Elia, Chiara; Pardi, Ruggero; Blasi, Francesco; Poli, Guido

doi:10.1182/blood-2008-02-138412

Cited by 12 publications

(24 citation statements)

References 77 publications

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“…Cell-to-cell contacts, cell adhesion to the substrate, and cell differentiation state enhance HIV replication (29)(30)(31). Adhesion molecules including integrins have been recognized as host factors that influence viral replication including HIV (6,8,10,11,(32)(33)(34). Moreover, we and others have demonstrated a role of integrin a v in HIV pathogenesis in MDMs (6,10,11).…”

Section: Discussionmentioning

confidence: 63%

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Ballana

Pauls

Clotet

et al. 2011

The Journal of Immunology

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Monocytes and macrophages are targets of HIV-1 infection and play critical roles in multiple aspects of viral pathogenesis. During the differentiation of monocytes to macrophages, adhesion molecules such as integrins are upregulated; therefore, they provide signals that control the process and subsequently may render macrophages more susceptible to HIV-1 infection. Previous work demonstrated that blocking αv-containing integrins triggered a signal transduction pathway leading to the inhibition of NF-κB–dependent HIV-1 transcription. In this paper, we show the influence of the different αv-coupled β integrins in HIV-1 replication in macrophages. Inhibition of β integrins, either by specific mAbs, small arginine-glycine-aspartic acid (RGD) mimetic compounds, or RNA interference, showed that integrin β5 was the major contributor to the integrin-mediated blockade of HIV-1 replication. Importantly, such inhibition did not induce changes in cell adhesion to the substrate. In conclusion, our results reveal a significant role of the integrin dimmer αvβ5 in HIV-1 infection of macrophages.

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Section: Discussionmentioning

confidence: 63%

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Ballana

Pauls

Clotet

et al. 2011

The Journal of Immunology

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“…A similar enrichment of a VCC-like structure was observed when D-U1 cells were stimulated with urokinase-type plasminogen activator (uPA), a multifunctional ligand playing a role in vascular hemostasis, tissue repair, and inflammation [43]. uPA mediated its effect via interaction with a glycosyl-phosphatidyl-inositol (GPI) anchored receptor (uPAR) requiring pairing with signalcompetent receptors for signal transduction.…”

Section: Expansion Of Vccs By Macrophage Stimulation With Extracellulmentioning

confidence: 71%

“…This uPA/uPAR effect on D-U1 cells was actually mediated by their association with the integrin CD11b/CD18 (Mac1), also known as complement receptor 3 (CR3). In fact, an anti-Mac1 antibody also induced expansion of a VCC-like structure in D-U1 cells [43]. Protein kinase C epsilon (PKCe) and RhoA activation were then shown to be responsible for this effect induced by uPA/uPAR [44].…”

Section: Expansion Of Vccs By Macrophage Stimulation With Extracellulmentioning

confidence: 98%

Immuno-Pharmacological Targeting of Virus-Containing Compartments in HIV-1-Infected Macrophages

Graziano

Vicenzi

Poli

2016

Trends in Microbiology

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“…; BioLegend) were used to inhibit interactions with CD11b/Mac-1, CD54/ICAM-1 or CD102/ICAM-2. M25 (PRYQHIGLVAMFRQNTG; disrupts interaction of CD11b/Mac-1 with uPAR 18 ) and its scrambled peptide scM25 (HQIPGAYRGVNQRFTML; 250 g in 150 L saline; i.a.) were kindly provided by Dr G. Arnold (LAFUGA, LudwigMaximilians-Universität München, Munich, Germany).…”

Section: Inhibitors and Antibodiesmentioning

confidence: 99%

Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor

et al. 2011

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Background-Urokinase-type plasminogen activator (uPA) has recently been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying mechanisms remain largely unclear. Methods and Results-Using in vivo microscopy on the mouse cremaster muscle, I/R-elicited firm adherence and transmigration of neutrophils were found to be significantly diminished in uPA-deficient mice and in mice treated with the uPA inhibitor WX-340, but not in uPA receptor (uPAR)-deficient mice. Interestingly, postischemic leukocyte responses were significantly reduced on blockade of the integrin CD11b/Mac-1, which also serves as uPAR receptor. Using a cell transfer technique, postischemic adherence and transmigration of wild-type leukocytes were significantly decreased in uPA-deficient animals, whereas uPA-deficient leukocytes exhibited a selectively reduced transmigration in wild-type animals. On I/R or stimulation with recombinant uPA, Ͼ90% of firmly adherent leukocytes colocalized with CD31-immunoreactive endothelial junctions as detected by in vivo fluorescence microscopy. In a model of hepatic I/R, treatment with WX-340 significantly attenuated postischemic neutrophil infiltration and tissue injury. Conclusions-Our data suggest that endothelial uPA promotes intravascular adherence, whereas leukocyte uPA facilitates the subsequent paracellular transmigration of neutrophils during I/R. This process is regulated via CD11b/Mac-1, and does not require uPAR. Pharmacological blockade of uPA interferes with these events and effectively attenuates postischemic tissue injury. (Circulation. 2011;124:1848-1859.)Key Words: ischemia Ⅲ leukocytes Ⅲ plasminogen activators Ⅲ reperfusion Ⅲ urokinase I schemia-reperfusion (I/R) injury is considered to be the most common cause of organ dysfunction and failure after myocardial infarction, hemorrhagic shock, and transplantation. Leukocyte infiltration of postischemic tissue is a key event in the pathogenesis of I/R injury. In this multistep cascade, a diversity of adhesion molecules, chemoattractants, and proteases are involved, regulating intravascular rolling and firm adherence as well as transendothelial migration of leukocytes to the reperfused tissue. [1][2][3][4] Clinical Perspective on p 1859Urokinase-type plasminogen activator (uPA) is a serine protease that has been implicated in a variety of physiological and pathophysiological processes. In this context, uPA is known to activate extracellular matrix-degrading enzymes and, through interaction with the urokinase receptor (uPAR; CD87), uPA is thought to induce intracellular signaling pathways, ultimately regulating cell adhesion and migration. 5 Moreover, uPA mediates the conversion of plasminogen to plasmin, which, in addition to its fibrinolytic properties, is also able to degrade components of the ECM as well as to activate intracellular signaling mechanisms. 6 Plasminogen activators, such as recombinant uPA, are therapeutically used for the activation of the fibrinolytic system during thrombembolic events. 7 Interestingl...

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Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells

Cited by 12 publications

References 77 publications

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Immuno-Pharmacological Targeting of Virus-Containing Compartments in HIV-1-Infected Macrophages

Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor

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