Differential Induction of the ADAM17 Regulators iRhom1 and 2 in Endothelial Cells.

Published on Dec 1, 2020in Frontiers in Cardiovascular Medicine6.05
· DOI :10.3389/FCVM.2020.610344
Aaron Babendreyer9
Estimated H-index: 9
,
Diana M. Rojas-González2
Estimated H-index: 2
(TUM: Technische Universität München)
+ 4 AuthorsAndreas Ludwig43
Estimated H-index: 43
Sources
Abstract
Background: Endothelial function significantly depends on the proteolytic release of surface expressed signal molecules, their receptors and adhesion molecules via the metalloproteinase ADAM17. The pseudoproteases iRhom1 and 2 independently function as adapter proteins for ADAM17 and are essential for the maturation, trafficking, and activity regulation of ADAM17. Bioinformatic data confirmed that immune cells predominantly express iRhom2 while endothelial cells preferentially express iRhom1. Objective: Here, we investigate possible reasons for higher iRhom1 expression and potential inflammatory regulation of iRhom2 in endothelial cells and analyze the consequences for ADAM17 maturation and function. Methods: Primary endothelial cells were cultured in absence and presence of flow with and without inflammatory cytokines (TNFα and INFγ). Regulation of iRhoms was studied by qPCR, involved signaling pathways were studied with transcriptional inhibitors and consequences were analyzed by assessment of ADAM17 maturation, surface expression and cleavage of the ADAM17 substrate junctional adhesion molecule JAM-A. Results: Endothelial iRhom1 is profoundly upregulated by physiological shear stress. This is accompanied by a homeostatic phenotype driven by the transcription factor KLF2 which is, however, only partially responsible for regulation of iRhom1. By contrast, iRhom2 is most prominently upregulated by inflammatory cytokines. This correlates with an inflammatory phenotype driven by the transcription factors NFκB and AP-1 of which AP-1 is most relevant for iRhom2 regulation. Finally, shear stress exposure and inflammatory stimulation have independent and no synergistic effects on ADAM17 maturation, surface expression and JAM-A shedding. Conclusion: Conditions of shear stress and inflammation differentially upregulate iRhom1 and 2 in primary endothelial cells which then results in independent regulation of ADAM17.
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#1Yiwei Zhao (XMU: Xinjiang Medical University)H-Index: 1
#2Peile Ren (XMU: Xinjiang Medical University)H-Index: 1
Last. Yong-Mei NieH-Index: 1
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Atherosclerosis is a significant cause of mortality and morbidity. Studies suggest that the chemokine receptor CX3CR1 plays a critical role in atherogenesis. Shear stress is an important mechanical force that affects blood vessel function. In this study, we investigated the effect of shear stress on CX3CR1 expression in vascular endothelial cells (VECs). First, cells were exposed to different shear stress and then CX3CR1 mRNA and protein were measured by quantitative RT-PCR and western blot anal...
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#1Ioanna Oikonomidi (IGC: Instituto Gulbenkian de Ciência)H-Index: 2
#2Emma Burbridge (IGC: Instituto Gulbenkian de Ciência)H-Index: 7
Last. Colin Adrain (IGC: Instituto Gulbenkian de Ciência)H-Index: 25
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Inflammation forms part of the body's defense system against pathogens, but if the system becomes faulty, it can cause problems linked to inflammatory and autoimmune diseases. Immune cells coordinate their activity using specific signaling molecules called cytokines. For example, the cytokine TNF is an important trigger of inflammation and is produced at the surface of immune cells. A specific enzyme called TACE is needed to release TNF, as well as other signaling molecules, including proteins t...
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#1Ulrike Künzel (University of Oxford)H-Index: 4
#2Adam G. Grieve (University of Oxford)H-Index: 13
Last. Matthew Freeman (University of Oxford)H-Index: 61
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Cells in the human body communicate with one another for many different reasons, including to help organs develop correctly and to produce a healthy reponse to injury and infection. Signalling proteins, such as growth factors and cytokines, form the main language of this communication. Initially, many growth factors and cytokines remain attached to the surface of the cell that made them. When cells need to send a message to another one, an enzyme called ADAM17 acts like a pair of scissors to rel...
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#1Ioanna Oikonomidi (IGC: Instituto Gulbenkian de Ciência)H-Index: 2
#2Emma Burbridge (IGC: Instituto Gulbenkian de Ciência)H-Index: 7
Last. Colin Adrain (IGC: Instituto Gulbenkian de Ciência)H-Index: 25
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#2Yiwei Zhao (XMU: Xinjiang Medical University)H-Index: 1
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Fractalkine (FKN) is a cytokine which plays an important role in atherosclerosis and other inflammatory diseases. Studies have shown that FKN induces integrin-independent leukocyte adhesion to primary endothelial cells under physiological flow conditions. Further, increased expression of FKN has been demonstrated in atherosclerotic lesions induced by low shear stress. However, the signal transduction mechanisms involved in low shear stress-induced FKN upregulation are not well characterized. In ...
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#1Ulrike Künzel (University of Oxford)H-Index: 4
#2Adam G. Grieve (University of Oxford)H-Index: 13
Last. Matthew Freeman (University of Oxford)H-Index: 61
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#1Min-Young Lee (Korea Research Institute of Bioscience and Biotechnology)H-Index: 2
#2Ju-Seong Kang (Korea Research Institute of Bioscience and Biotechnology)H-Index: 1
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: Rhomboid family member 2 gene (Rhbdf2) is an inactive homologue lacking essential catalytic residues of rhomboid intramembrane serine proteases. The protein is necessary for maturation of tumor necrosis factor-alpha (TNF-α) converting enzyme, which is the molecule responsible for the release of TNF-α. In this study, Rhbdf2 knockout (KO) mice were produced by CRISPR/CAS9. To see the effects of the failure of TNF-α release induced by Rhbdf2 gene KO, collagen-induced arthritis (CIA), which is the...
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#2Ioanna Oikonomidi (IGC: Instituto Gulbenkian de Ciência)H-Index: 2
Last. Colin Adrain (IGC: Instituto Gulbenkian de Ciência)H-Index: 25
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Summary Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE b...
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#1Adam G. Grieve (University of Oxford)H-Index: 13
#2Hongmei Xu (University of Oxford)H-Index: 2
Last. Matthew Freeman (University of Oxford)H-Index: 61
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Injury or infection can cause tissues in the body to become inflamed. The immune system triggers this inflammation to help repair the injury or fight the infection. A signal molecule known as TNF – which is produced by immune cells called macrophages – triggers inflammation. This protein is normally attached to the surface of the macrophage, and it only activates inflammation once it has been cut free. An enzyme called TACE cuts and releases TNF from the surface of macrophages. This enzyme is ma...
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#1Adam G. Grieve (University of Oxford)H-Index: 13
#2Hongmei Xu (University of Oxford)H-Index: 2
Last. Matthew Freeman (University of Oxford)H-Index: 61
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A disintegrin and metalloproteases (ADAMs) are key mediators of cell signaling by ectodomain shedding of various growth factors, cytokines, receptors and adhesion molecules at the cellular membrane. ADAMs regulate cell proliferation, cell growth, inflammation, and other regular cellular processes. ADAM17, the most extensively studied ADAM family member, is also known as tumor necrosis factor (TNF)-α converting enzyme (TACE). ADAMs-mediated shedding of cytokines such as TNF-α orchestrates immune ...
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