ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling

Sun, Chongxiu; Wu, Mack H.; Guo, Mingzhang; Day, Mark L.; Lee, Eugene S.; Yuan, Sarah Y.

doi:10.1093/cvr/cvq060

Cited by 73 publications

(61 citation statements)

References 44 publications

(69 reference statements)

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“…Albumin transendothelial flux and TER. As indicators of barrier properties, albumin permeability across endothelial monolayers and transendothelial electrical resistance (TER) were measured as previously described (27). For albumin permeability, endothelial cells (ECs) were grown to confluence on a 0.3-m pore Transwell membrane, and followed by FITC-labeled albumin (15 mM) added to the top chamber.…”

Section: Animals Adam15mentioning

confidence: 99%

“…However, these structures can be degraded or shed by proteases like ADAMs (8,26) or may undergo conformational changes in response to pathological signaling (12,18,31). In HUVEC monolayers, ADAM15 is necessary for both endothelial hyperpermeability and increased neutrophil transmigration in response to thrombin exposure (28). Moreover, these ADAM15-dependent effects are mediated largely by endothelial intracellular signaling through Src kinase and extracellular regulated kinase (ERK)-1/2, and not through receptor ectodomain shedding.…”

mentioning

confidence: 99%

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ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

Sun

Beard

McLean

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Sun C, Beard RS Jr, McLean DL, Rigor RR, Konia T, Wu MH, Yuan SY. ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice. Am J Physiol Lung Cell Mol Physiol 304: L135-L142, 2013. First published November 16, 2012 doi:10.1152/ajplung.00133.2012.-ADAM15 is a disintegrin and metalloprotease recently implicated in cancer and chronic immune disorders. We have recently characterized ADAM15 as a mediator of endothelial barrier dysfunction. Whether this molecule contributes to acute inflammation has not been evaluated. The purpose of this study was to investigate the role of ADAM15 in mediating pulmonary microvascular leakage during acute inflammatory injury. Immunofluorescent staining and Western blotting revealed that the endothelium was the main source of ADAM15 in lung tissue. In a mouse model of acute lung injury induced by lipopolysaccharide (LPS), upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration. The LPS-induced inflammatory injury, as demonstrated by bronchoalveolar lavage neutrophil count, lung wet-to-dry weight ratio, and myeloperoxidase activity, was significantly attenuated in Adam15 Ϫ/Ϫ mice. Studies with primary cell culture demonstrated abundant ADAM15 expression in endothelial cells (ECs) of mouse lung but not in neutrophils. Deficiency of ADAM15 in ECs had no obvious effect on basal permeability but significantly attenuated hyperpermeability response to LPS as evidenced by albumin flux assay and measurements of transendothelial electrical resistance, respectively. ADAM15 deficiency also reduced neutrophil chemotactic transmigration across endothelial barriers in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). Rescue expression of ADAM15 in Adam15 Ϫ/Ϫ ECs restored neutrophil transendothelial migration. These data indicate that ADAM15 upregulation contributes to inflammatory lung injury by promoting endothelial hyperpermeability and neutrophil transmigration. vascular permeability; metalloproteinase; endothelial dysfunction; inflammation THE ADAMS (a disintegrin and metalloproteinase) are multifunctional transmembrane glycoproteins that are involved in a variety of biological processes (5, 17). In general, ADAMs are metalloproteinases that are capable of cleaving cell surface protein ectodomains and inducing signaling events through receptor shedding, and/or outside-in signaling (8,26). ADAM15 is a less studied ADAM isoform that is found in human vein endothelium (13) and is associated with certain types of cancer and chronic inflammatory or immunological disorders (5, 14, 21). In particular, ADAM15 supports cancer metastasis by promoting tumor cell migration and angiogenesis (21,24). Increased ADAM15 expression is also detected in atherosclerotic lesions, rheumatoid synovium, angiogenic retinas, and the intestines of patients with inflammatory bowl disease (1, 3-5). This suggests that increased ADAM15 expression is involved in a variety of inflammatory conditions.Our rec...

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Section: Animals Adam15mentioning

confidence: 99%

mentioning

confidence: 99%

ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

Sun

Beard

McLean

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…3D and E). It is known that cytoplasmic tail of phosphorylated ADAM15 interacts with Src (Maretzky et al, 2009;Poghosyan et al, 2002), which is up-stream to MEK1/2 (Guo and Giancotti, 2004), leading to Erk1/2 signaling pathway (Sun et al, 2010). In this study, phosphorylation of Erk was not affected by the cell to cell interaction via ADAM15 and integrins ( Fig.…”

Section: Discussionmentioning

confidence: 54%

The Cell to Cell Interaction of Breast Cancer Cells Regulates Cancer Invasion via Adam15

Ota

Ikesue

Matsui

et al. 2012

American Journal of Immunology

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Increasing evidence suggests that a disintegrin and metalloproteinase 15 (ADAM15) have essential roles in the process of cancer metastasis via degradation of the extracellular matrix and binding to integrins. Among them, ADAM15 possesses an Arg-Gly-Asp (RGD) sequence within its disintegrin domain (d.d., hereafter) and binds to RGD recognizing-integrins such as αvβ3 and α5β1 and also interacts with integrin α9β1 in RGD-independent manner. Although these integrins play important roles in the process of cancer metastasis, the role of the interactions between ADAM15 and integrins during processes of cancer metastasis remains to be elucidated. We produced the specific antibody (8F7) that interferes with the interaction of human ADAM15 and integrin receptors and performed in vitro aggregation assay, invasion assay, proliferation assay, proteinase activity assay and cell-cell adhesion assay. 8F7 inhibited tumor cell aggregation, invasion and migration, but not proliferation of breast cancer cells and proteinase activity of ADAM15. Furthermore, the interactions between ADAM15 and integrin receptors induced collective cell migration, phosphorylation of Akt, which was known to promote invasion of breast cancer cells. These data suggested that the binding of ADAM15 to αvβ3 or α9β1 integrins through its d.d. Induces cell aggregation, migration and invasion of human breast cancer cells with concomitant activation of Akt signaling pathway.

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“…Interestingly, upregulation of ADAM15 expression has previously been reported in cells treated with proinflammatory cytokines and in tissues of inflammatory diseases (34). Overexpression of ADAM15 has also been shown to increase ERK1/2 activation in endothelial cells (35). Activation of TRIF leads to proinflammatory cytokine induction, which is dependent on NF-kB and MAPK activation (22).…”

Section: Common Targets/regulator Network Of Adam15 and Trifmentioning

confidence: 95%

TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

Ahmed

Maratha

Butt

et al. 2013

The Journal of Immunology

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TLRs are a group of pattern-recognition receptors that play a crucial role in danger recognition and induction of the innate immune response against bacterial and viral infections. The TLR adaptor molecule, Toll/IL-1R domain-containing adaptor inducing IFN (TRIF), facilitates TLR3 and TLR4 signaling and concomitant activation of the transcription factors, NF-κB and IFN regulatory factor 3, leading to proinflammatory cytokine production. Whereas numerous studies have been undertaken toward understanding the role of TRIF in TLR signaling, little is known about the signaling components that regulate TRIF-dependent TLR signaling. To this end, TRIF-interacting partners were identified by immunoprecipitation of the TRIF signaling complex, followed by protein identification using liquid chromatography mass spectrometry. Following stimulation of cells with a TLR3 or TLR4 ligand, we identified a disintegrin and metalloprotease (ADAM)15 as a novel TRIF-interacting partner. Toward the functional characterization of the TRIF:ADAM15 interaction, we show that ADAM15 acts as a negative regulator of TRIF-mediated NF-κB and IFN-β reporter gene activity. Also, suppression of ADAM15 expression enhanced polyriboinosinic polyribocytidylic acid and LPS-mediated proinflammatory cytokine production via TRIF. In addition, suppression of ADAM15 expression enhanced rhinovirus 16 and vesicular stomatitis virus–mediated proinflammatory cytokine production. Interestingly, ADAM15 mediated the proteolytic cleavage of TRIF. Thus, ADAM15 serves to curtail TRIF-dependent TLR3 and TLR4 signaling and, in doing so, protects the host from excessive production of proinflammatory cytokines and matrix metalloproteinases. In conclusion, to our knowledge, our study clearly shows for the first time that ADAM15 plays an unexpected role in TLR signaling, acting as an anti-inflammatory molecule through impairment of TRIF-mediated TLR signaling.

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ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling

Abstract: The data provide evidence for a novel function of ADAM15 in regulating endothelial barrier properties. The mechanisms of ADAM15-induced hyperpermeability involve Src/ERK1/2 signalling independent of junction molecule shedding.

Cited by 73 publications

References 44 publications

ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

The Cell to Cell Interaction of Breast Cancer Cells Regulates Cancer Invasion via Adam15

TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

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