Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response

Li, Xuehua; Syrovets, Tatiana; Genze, Felicitas; Pitterle, Kai; Oberhuber, Alexander; Orend, Karl-Heinz; Simmet, Thomas

doi:10.1161/atvbaha.109.202044

Cited by 48 publications

(60 citation statements)

References 45 publications

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“…For instance, although both Akt1 and Akt2 have been shown to regulate palladin, Akt1 regulates its phosphorylation (Chin and Toker, 2010a), whereas Akt2 controls its expression (Chin and Toker, 2010b), illustrating that these two isoforms of Akt1 can have differential effects on a common substrate. Furthermore, light-induced actin reorganization in rod photoreceptor cells is dependent on Akt1 only (Li et al, 2008), whereas plasmintriggered chemotaxis of dendritic cells is an Akt2-dependent event (Li et al, 2010). Thus, further studies are necessary to define whether these proteins regulate BTB restructuring by different means or different effectors downstream, or whether one is more important than the other in regulating BTB dynamics.…”

Section: Discussionmentioning

confidence: 99%

rpS6 regulates blood-testis barrier dynamics via its effects on MMP-9 mediated by Akt signaling

Mok

Mruk

Cheng

2014

Journal of Cell Science

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Mammalian target of rapamycin complex 1 (mTORC1) is an emerging regulator of blood-tissue barriers that utilizes ribosomal protein S6 (rpS6) as the downstream signaling molecule. To explore the role of rpS6 in blood-testis barrier (BTB) function, a constitutively active quadruple rpS6 phosphomimetic mutant was constructed in mammalian expression vector and overexpressed in Sertoli cells cultured in vitro that mimicked the BTB in vivo. Using this quadruple phosphomimetic mutant, phosphorylated (p)-rpS6 was shown to disrupt IGF-1/insulin signaling, thereby abolishing Akt phosphorylation, which led to an induction of MMP-9. This increase in MMP-9 secretion perturbed the Sertoli cell tight junction permeability barrier by proteolysis-mediated downregulation of tight junction proteins at the BTB. These findings were confirmed by the use of a specific MMP-9 inhibitor that blocked the disruption of the tight junction permeability barrier by the rpS6 mutant. Additionally, RNA interference (RNAi)-mediated Akt silencing was able to mimic the results of rpS6 mutant overexpression in Sertoli cells, further confirming this p-rpS6-Akt-MMP-9 signaling pathway. In conclusion, these data support a new concept of mTORC1-mediated BTB regulation, that is possibly also applicable to other blood-tissue barriers.

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Section: Discussionmentioning

confidence: 99%

rpS6 regulates blood-testis barrier dynamics via its effects on MMP-9 mediated by Akt signaling

Mok

Mruk

Cheng

2014

Journal of Cell Science

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“…Some macrophages were treated with DMEM only as an additional control. To test whether Plg activation was sufficient to up-regulate S100A9, macrophages were also treated with DMEM plus plasmin (Hematologic Technologies) or with nontransgenic conditioned medium plus plasmin (100 nM, a concentration at which plasmin activates signaling in both endothelial and dendritic cells) (36,37). After 6 h, the medium was aspirated, and the treated macrophages were washed twice with PBS to remove any cells or debris that might have been carried over with the conditioned medium.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Farris

Krishnan

et al. 2011

Journal of Biological Chemistry

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Data from clinical studies, cell culture, and animal models implicate the urokinase plasminogen activator (uPA)/uPA receptor (uPAR)/plasminogen system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/uPAR/plasminogen stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression and mice genetically deficient in uPAR to elucidate mechanisms of uPA/uPAR/plasminogen-accelerated atherosclerosis and aneurysm formation. We found that macrophage-specific uPA overexpression accelerates atherosclerosis and causes aortic root dilation in fat-fed Ldlr ؊/؊ mice (as we previously reported in Apoe ؊/؊ mice). Macrophage-expressed uPA accelerates atherosclerosis by stimulation of lesion progression rather than initiation and causes disproportionate lipid accumulation in early lesions. uPA-accelerated atherosclerosis and aortic dilation are largely, if not completely, independent of uPAR. In the absence of uPA overexpression, however, uPAR contributes modestly to both atherosclerosis and aortic dilation. Microarray studies identified S100A8 and S100A9 mRNA as the most highly up-regulated transcripts in uPA-overexpressing macrophages; up-regulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also up-regulated in the aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is up-regulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Macrophage microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm in a second animal model that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also reveal uPAR independence of these actions and implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease.Atherosclerosis and aneurysm formation are common cardiovascular diseases that have a significant impact on human health. Atherosclerosis is characterized by accumulation in the inner blood vessel wall of cellular and matrix-rich plaques that cause vessel lumen narrowing and tissue ischemia. Clinical events in patients with atherosclerosis (e.g. heart attacks and strokes) are typically caused by rupture of atherosclerotic plaques with superimposed thrombosis that occludes the vessel lumen (1). In contrast, aneurysms are abnormal expansions of a blood vessel that can lead to complete disruption of the vessel wall, causing sudden death (2). The molecular mechanisms that contribute to plaque growth, plaque rupture, and aneurysm formation are incompletely understood. Elucidation of these mechanisms should enable the development of novel, targeted therapies that improve human health.We and others (3) have hypothesized that the urokinase plasminogen activator (uPA) 6 /plasminoge...

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“…Plasmin is a potent inflammatory mediator and inducer of immune responses. In vitro studies from our lab indicated that plasmin generated at sites of inflammation such as atherosclerotic lesions might be capable of eliciting chemotaxis of human monocytes [4] and dentritic cells (DCs) [5] and stimulating cytokines production from monocytes [4], macrophages [6], and DCs [7], which contribute to inflammation. A recent clinical study revealed that the enhanced plasmin activity is correlated with the degree of lesion complexity in human carotid plaques [8] and a clinical atherosclerosis case report presented that aggravated plasmin generation might indeed lead to cardiovascular complications [9].…”

Section: Introductionmentioning

confidence: 99%

Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages

Laumonnier

Syrovets

et al. 2013

ABBS

Self Cite

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In the present study, monocyte-derived human macrophages were differentiated from buffy coats. Naïve CD4 1 T-cells enriched from peripheral blood mononuclear cells using anti-CD4 magnetic beads and the autoMACS separation system were polarized under T-helper 17 (Th17)-promoting conditions for 6 days to get Th17 cells. The frequency of Th17 cell differentiation and the expression of C-C chemokine receptor type 6 (CCR6) on Th17 cells were investigated by flow cytometry. Plasmin-triggered induction of macrophage inflammatory protein-3alpha/C-C chemokine ligand 20 (CCL20) genes in macrophages was assessed by reverse transcription-polymerase chain reaction, and secreted protein levels were measured by enzymelinked immunosorbent assay. Th17 cell migration induced by CCL20 secreted from plasmin-stimulated macrophages was tested in vitro by chemotaxis using a transwell system. These results demonstrate that plasmin triggers the expression of chemokine CCL20 messenger RNA and the release of CCL20 protein in human monocyte-derived macrophages, which critically depend on the proteolytic activity of plasmin and activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. Expression of CCR6 was detected on 87.23 + + + + + 8.6% of Th17 cells in vitro. Similar to chemotaxis triggered by recombinant human CCL20, supernatants collected from plasmin-stimulated macrophage-induced chemotactic migration of Th17 cells, which could be inhibited by an anti-CCL20 neutralizing antibody. These results suggest that plasmin generated in inflamed tissues might elicit production of chemokine CCL20 by human macrophages leading to the recruitment of CCR6 positive Th17 cells to the inflammatory sites.

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Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response

Cited by 48 publications

References 45 publications

rpS6 regulates blood-testis barrier dynamics via its effects on MMP-9 mediated by Akt signaling

rpS6 regulates blood-testis barrier dynamics via its effects on MMP-9 mediated by Akt signaling

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages

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