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Article: Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages.

Petersen, Steen Vang / Poulsen, Nanna Bach / Linneberg Matthiesen, Cecilie / Vilhardt, Frederik

2021 Volume 10, Issue 2

Abstract: Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting ... ...

Abstract	Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells.
Language	English
Publishing date	2021-01-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10020172
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

Petersen, Steen Vang / Poulsen, Nanna Bach / Linneberg Matthiesen, Cecilie / Vilhardt, Frederik

Antioxidants. 2021 Jan. 25, v. 10, no. 2

2021

Abstract	Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells.
Keywords	NAD(P)H oxidase (H2O2-forming) ; autocrine signaling ; exosomes ; exports ; guanosinetriphosphatase ; hydrogen peroxide ; macrophage activation ; macrophages ; oxidants ; pathogens ; sphingolipids ; transcription (genetics)
Language	English
Dates of publication	2021-0125
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10020172
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing.

Linneberg, Cecilie / Toft, Christian Liebst Frisk / Kjaer-Sorensen, Kasper / Laursen, Lisbeth S

Scientific reports

2019 Volume 9, Issue 1, Page(s) 3716

Abstract: Normal brain development depends on tight temporal and spatial regulation of connections between cells. Mutations in L1cam, a member of the immunoglobulin (Ig) superfamily that mediate cell-cell contacts through homo- and heterophilic interactions, are ... ...

Abstract	Normal brain development depends on tight temporal and spatial regulation of connections between cells. Mutations in L1cam, a member of the immunoglobulin (Ig) superfamily that mediate cell-cell contacts through homo- and heterophilic interactions, are associated with several developmental abnormalities of the nervous system, including mental retardation, limb spasticity, hydrocephalus, and corpus callosum aplasia. L1cam has been reported to be shed from the cell surface, but the significance of this during different phases of brain development is unknown. We here show that ADAM10-mediated shedding of L1cam is regulated by its fibronectin type III (FNIII) domains. Specifically, the third FNIII domain is important for maintaining a conformation where access to a membrane proximal cleavage site is restricted. To define the role of ADAM10/17/BACE1-mediated shedding of L1cam during brain development, we used a zebrafish model system. Knockdown of the zebrafish, l1camb, caused hydrocephalus, defects in axonal outgrowth, and myelination abnormalities. Rescue experiments with proteinase-resistant and soluble L1cam variants showed that proteolytic cleavage is not required for normal axonal outgrowth and development of the ventricular system. In contrast, metalloproteinase-mediated shedding is required for efficient myelination, and only specific fragments are able to mediate this stimulatory function of the shedded L1cam.
MeSH term(s)	ADAM Proteins/metabolism ; Animals ; Aspartic Acid Endopeptidases/metabolism ; Brain/growth & development ; Brain/metabolism ; Disease Models, Animal ; Gene Knockout Techniques ; HEK293 Cells ; Humans ; Hydrocephalus/genetics ; Hydrocephalus/metabolism ; Neural Cell Adhesion Molecule L1/chemistry ; Neural Cell Adhesion Molecule L1/genetics ; Neural Cell Adhesion Molecule L1/metabolism ; Proteolysis ; Zebrafish ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
Chemical Substances	L1CAM protein, human ; Neural Cell Adhesion Molecule L1 ; Zebrafish Proteins ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; ADAM Proteins (EC 3.4.24.-)
Language	English
Publishing date	2019-03-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-39884-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing

Cecilie Linneberg / Christian Liebst Frisk Toft / Kasper Kjaer-Sorensen / Lisbeth S. Laursen

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 14

Abstract: Abstract Normal brain development depends on tight temporal and spatial regulation of connections between cells. Mutations in L1cam, a member of the immunoglobulin (Ig) superfamily that mediate cell-cell contacts through homo- and heterophilic ... ...

Abstract	Abstract Normal brain development depends on tight temporal and spatial regulation of connections between cells. Mutations in L1cam, a member of the immunoglobulin (Ig) superfamily that mediate cell-cell contacts through homo- and heterophilic interactions, are associated with several developmental abnormalities of the nervous system, including mental retardation, limb spasticity, hydrocephalus, and corpus callosum aplasia. L1cam has been reported to be shed from the cell surface, but the significance of this during different phases of brain development is unknown. We here show that ADAM10-mediated shedding of L1cam is regulated by its fibronectin type III (FNIII) domains. Specifically, the third FNIII domain is important for maintaining a conformation where access to a membrane proximal cleavage site is restricted. To define the role of ADAM10/17/BACE1-mediated shedding of L1cam during brain development, we used a zebrafish model system. Knockdown of the zebrafish, l1camb, caused hydrocephalus, defects in axonal outgrowth, and myelination abnormalities. Rescue experiments with proteinase-resistant and soluble L1cam variants showed that proteolytic cleavage is not required for normal axonal outgrowth and development of the ventricular system. In contrast, metalloproteinase-mediated shedding is required for efficient myelination, and only specific fragments are able to mediate this stimulatory function of the shedded L1cam.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling.

Linneberg, Cecilie / Harboe, Mette / Laursen, Lisbeth S

ASN neuro

2015 Volume 7, Issue 5

Abstract: In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward ... ...

Abstract	In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.
MeSH term(s)	Animals ; Axons/physiology ; Cell Communication/physiology ; Cell Differentiation/physiology ; Cells, Cultured ; Cerebral Cortex/physiology ; Coculture Techniques ; Ephrins/metabolism ; Ganglia, Spinal/growth & development ; Ganglia, Spinal/physiology ; Integrins/metabolism ; Myelin Sheath/physiology ; Neural Stem Cells/physiology ; Oligodendroglia/physiology ; Rats ; Receptors, Eph Family/metabolism ; Signal Transduction/physiology
Chemical Substances	Ephrins ; Integrins ; Receptors, Eph Family (EC 2.7.10.1)
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2485467-0
ISSN	1759-0914 ; 1759-0914
ISSN (online)	1759-0914
ISSN	1759-0914
DOI	10.1177/1759091415602859
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

Prins, Bram P / Mead, Timothy J / Brody, Jennifer A / Sveinbjornsson, Gardar / Ntalla, Ioanna / Bihlmeyer, Nathan A / van den Berg, Marten / Bork-Jensen, Jette / Cappellani, Stefania / Van Duijvenboden, Stefan / Klena, Nikolai T / Gabriel, George C / Liu, Xiaoqin / Gulec, Cagri / Grarup, Niels / Haessler, Jeffrey / Hall, Leanne M / Iorio, Annamaria / Isaacs, Aaron /

Li-Gao, Ruifang / Lin, Honghuang / Liu, Ching-Ti / Lyytikäinen, Leo-Pekka / Marten, Jonathan / Mei, Hao / Müller-Nurasyid, Martina / Orini, Michele / Padmanabhan, Sandosh / Radmanesh, Farid / Ramirez, Julia / Robino, Antonietta / Schwartz, Molly / van Setten, Jessica / Smith, Albert V / Verweij, Niek / Warren, Helen R / Weiss, Stefan / Alonso, Alvaro / Arnar, David O / Bots, Michiel L / de Boer, Rudolf A / Dominiczak, Anna F / Eijgelsheim, Mark / Ellinor, Patrick T / Guo, Xiuqing / Felix, Stephan B / Harris, Tamara B / Hayward, Caroline / Heckbert, Susan R / Huang, Paul L / Jukema, J W / Kähönen, Mika / Kors, Jan A / Lambiase, Pier D / Launer, Lenore J / Li, Man / Linneberg, Allan / Nelson, Christopher P / Pedersen, Oluf / Perez, Marco / Peters, Annette / Polasek, Ozren / Psaty, Bruce M / Raitakari, Olli T / Rice, Kenneth M / Rotter, Jerome I / Sinner, Moritz F / Soliman, Elsayed Z / Spector, Tim D / Strauch, Konstantin / Thorsteinsdottir, Unnur / Tinker, Andrew / Trompet, Stella / Uitterlinden, André / Vaartjes, Ilonca / van der Meer, Peter / Völker, Uwe / Völzke, Henry / Waldenberger, Melanie / Wilson, James G / Xie, Zhijun / Asselbergs, Folkert W / Dörr, Marcus / van Duijn, Cornelia M / Gasparini, Paolo / Gudbjartsson, Daniel F / Gudnason, Vilmundur / Hansen, Torben / Kääb, Stefan / Kanters, Jørgen K / Kooperberg, Charles / Lehtimäki, Terho / Lin, Henry J / Lubitz, Steven A / Mook-Kanamori, Dennis O / Conti, Francesco J / Newton-Cheh, Christopher H / Rosand, Jonathan / Rudan, Igor / Samani, Nilesh J / Sinagra, Gianfranco / Smith, Blair H / Holm, Hilma / Stricker, Bruno H / Ulivi, Sheila / Sotoodehnia, Nona / Apte, Suneel S / van der Harst, Pim / Stefansson, Kari / Munroe, Patricia B / Arking, Dan E / Lo, Cecilia W / Jamshidi, Yalda

Genome biology

2018 Volume 19, Issue 1, Page(s) 87

Abstract: Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants ... ...

Abstract	Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
MeSH term(s)	ADAMTS Proteins/genetics ; Animals ; Black People ; Connexin 43/genetics ; Electrocardiography ; Exome ; Female ; Gene Expression ; Gene Expression Profiling ; Genetic Loci ; Genome-Wide Association Study ; Heart Conduction System/metabolism ; Heart Conduction System/physiopathology ; Humans ; Male ; Mice ; Middle Aged ; Myocardium/metabolism ; Myocardium/pathology ; Open Reading Frames ; Polymorphism, Single Nucleotide ; White People ; Exome Sequencing
Chemical Substances	Connexin 43 ; GJA1 protein, human ; ADAMTS Proteins (EC 3.4.24.-) ; Adamts6 protein, human (EC 3.4.24.-)
Language	English
Publishing date	2018-07-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-018-1457-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Li-Gao, Ruifang / Lin, Honghuang / Liu, Ching-Ti / Lyytikäinen, Leo-Pekka / Marten, Jonathan / Mei, Hao / Müller-Nurasyid, Martina / Orini, Michele / Padmanabhan, Sandosh / Radmanesh, Farid / Ramirez, Julia / Robino, Antonietta / Schwartz, Molly / van Setten, Jessica / Smith, Albert V / Verweij, Niek / Warren, Helen R / Weiss, Stefan / Alonso, Alvaro / Arnar, David O / Bots, Michiel L / de Boer, Rudolf A / Dominiczak, Anna F / Eijgelsheim, Mark / Ellinor, Patrick T / Guo, Xiuqing / Felix, Stephan B / Harris, Tamara B / Hayward, Caroline / Heckbert, Susan R / Huang, Paul L / Jukema, J. W / Kähönen, Mika / Kors, Jan A / Lambiase, Pier D / Launer, Lenore J / Li, Man / Linneberg, Allan / Nelson, Christopher P / Pedersen, Oluf / Perez, Marco / Peters, Annette / Polasek, Ozren / Psaty, Bruce M / Raitakari, Olli T / Rice, Kenneth M / Rotter, Jerome I / Sinner, Moritz F / Soliman, Elsayed Z / Spector, Tim D / Strauch, Konstantin / Thorsteinsdottir, Unnur / Tinker, Andrew / Trompet, Stella / Uitterlinden, André / Vaartjes, Ilonca / van der Meer, Peter / Völker, Uwe / Völzke, Henry / Waldenberger, Melanie / Wilson, James G / Xie, Zhijun / Asselbergs, Folkert W / Dörr, Marcus / van Duijn, Cornelia M / Gasparini, Paolo / Gudbjartsson, Daniel F / Gudnason, Vilmundur / Hansen, Torben / Kääb, Stefan / Kanters, Jørgen K / Kooperberg, Charles / Lehtimäki, Terho / Lin, Henry J / Lubitz, Steven A / Mook-Kanamori, Dennis O / Conti, Francesco J / Newton-Cheh, Christopher H / Rosand, Jonathan / Rudan, Igor / Samani, Nilesh J / Sinagra, Gianfranco / Smith, Blair H / Holm, Hilma / Stricker, Bruno H / Ulivi, Sheila / Sotoodehnia, Nona / Apte, Suneel S / van der Harst, Pim / Stefansson, Kari / Munroe, Patricia B / Arking, Dan E / Lo, Cecilia W / Jamshidi, Yalda

Genome biology. 2018 Dec., v. 19, no. 1

2018

Abstract: BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants ... ...

Abstract	BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Keywords	Africans ; Whites ; ancestry ; cardiac output ; connexins ; death ; electrocardiography ; gap junctions ; genome-wide association study ; genotype ; heart failure ; loci ; meta-analysis ; metalloproteinases ; mice ; secretion ; United Kingdom
Language	English
Dates of publication	2018-12
Size	p. 87.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6914 ; 1465-6906
ISSN (online)	1474-760X ; 1465-6914
ISSN	1465-6906
DOI	10.1186/s13059-018-1457-6
Database	NAL-Catalogue (AGRICOLA)

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Article: Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages.

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Article: Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

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Article ; Online: L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing.

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Article ; Online: L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing

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Article ; Online: Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling.

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Article ; Online: Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

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Article: Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

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