Publications by authors named "Andreas Ludwig"

172 Publications

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

Front Cardiovasc Med 2020 1;7:610344. Epub 2020 Dec 1.

Institute of Molecular Pharmacology, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.

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. 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. 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. 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. 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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http://dx.doi.org/10.3389/fcvm.2020.610344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736406PMC
December 2020

Expression levels of the metalloproteinase ADAM8 critically regulate proliferation, migration and malignant signalling events in hepatoma cells.

J Cell Mol Med 2021 Feb 13;25(4):1982-1999. Epub 2020 Dec 13.

Institute of Molecular Pharmacology, RWTH Aachen University, Aachen, Germany.

Hepatocellular carcinoma (HCC) is one of the most common metastatic tumours. Tumour growth and metastasis depend on the induction of cell proliferation and migration by various mediators. Here, we report that the A Disintegrin and Metalloproteinase (ADAM) 8 is highly expressed in murine HCC tissues as well as in murine and human hepatoma cell lines Hepa1-6 and HepG2, respectively. To establish a dose-dependent role of different ADAM8 expression levels for HCC progression, ADAM8 expression was either reduced via shRNA- or siRNA-mediated knockdown or increased by using a retroviral overexpression vector. These two complementary approaches revealed that ADAM8 expression levels correlated positively with proliferation, clonogenicity, migration and matrix invasion and negatively with apoptosis of hepatoma cells. Furthermore, the analysis of pro-migratory and proliferative signalling pathways revealed that ADAM8 expression level was positively associated with expression of β1 integrin as well as with the activation of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), Src kinase and Rho A GTPase. Finally, up-regulation of promigatory signalling and cell migration was also seen with a proteolytically inactive ADAM8 mutant. These findings reveal that ADAM8 is critically up-regulated in hepatoma cells contributes to cell proliferation and survival and furthermore induces pro-migratory signalling pathways independently of its proteolytic activity. By this, ADAM8 can promote cell functions most relevant for HCC growth and metastasis.
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http://dx.doi.org/10.1111/jcmm.16015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882935PMC
February 2021

Mechanic Forces Promote Brain Endothelial Activation by SARS-CoV-2 Spike Protein.

Stroke 2021 01 9;52(1):271-273. Epub 2020 Nov 9.

Institute of Molecular Pharmacology, RWTH Aachen University, Germany.

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http://dx.doi.org/10.1161/STROKEAHA.120.033119DOI Listing
January 2021

Inflammatory Responses of Astrocytes Are Independent from Lipocalin 2.

J Mol Neurosci 2020 Sep 21. Epub 2020 Sep 21.

Institute of Neuroanatomy, RWTH University Hospital Aachen, Aachen, Germany.

The central nervous system (CNS) responds to diverse neurologic injuries with a vigorous activation of astrocytes. In addition to their role in the maintenance of CNS homeostasis and neuronal function, astrocytes are thought to participate in the regulation of innate and adaptive immune responses in the CNS. Following antigen recognition, reactive astrocytes may participate in the initiation of innate immune responses, and modulate adaptive immune response leading to the recruitment of peripheral immune cells. Among activation, astrocytes undergo morphological changes and express several molecules, e.g., chemokines. Lipocalin 2 (LCN2) is involved in the control of innate immune responses, regulation of excess iron, and reactive oxygen production. Here, we investigated the influence of LCN2 on basic astrocytic functions linked to inflammatory responses. In vitro studies revealed a similar chemokine expression pattern in wild-type and Lcn2-deficient astrocyte cultures after treatment with lipopolysaccharides (LPS). Increased wound closure and morphological changes upon LPS treatment are independent of Lcn2 expression. We conclude that LCN2 is not necessary for basic astrocytic functions in the context of inflammation. However, CNS-derived LCN2 might have a regulatory effect on other cells, e.g., endothelial cells of the blood-brain barrier.
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http://dx.doi.org/10.1007/s12031-020-01712-7DOI Listing
September 2020

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner.

Int J Mol Sci 2020 Aug 19;21(17). Epub 2020 Aug 19.

Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany.

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria ( and , respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of . The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.
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http://dx.doi.org/10.3390/ijms21175978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503280PMC
August 2020

Boron Effect on Sugar-Based Organogelators.

Chemistry 2020 Nov 29;26(61):13927-13934. Epub 2020 Sep 29.

Ecole Nationale Supérieure de Chimie de Rennes, CNRS, ISCR-UMR6226, Université de Rennes, 35000, Rennes, France.

The reaction of several alkylglucosides with phenyl boronic acid permitted easy access to a series of alkylglucoside phenyl boronate derivatives. This type of compound has structures similar to those of known benzylidene glucoside organogelators except for the presence of a boronate function in place of the acetal one. Low to very low concentrations of these amphiphilic molecules produced gelation of several organic solvents. The rheological properties of the corresponding soft materials characterized them as elastic solids. They were further characterized by SEM to obtain more information on their morphologies and by SAXS to determine the type of self-assembly involved within the gels. The sensitivity of the boronate function towards hydrolysis was also investigated. We demonstrated that a small amount of water (5 % v/v) was sufficient to disrupt the organogels leading to the original alkylglucoside and phenyl boronic acid; an important difference with the stable benzylidene-based organogelators. Such water-sensitive boronated organogelators could be suitable substances for the preparation of smart soft material for topical drug delivery.
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http://dx.doi.org/10.1002/chem.202001970DOI Listing
November 2020

The metalloproteinase ADAM10 requires its activity to sustain surface expression.

Cell Mol Life Sci 2021 Jan 5;78(2):715-732. Epub 2020 May 5.

Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.

The metalloproteinase ADAM10 critically contributes to development, inflammation, and cancer and can be controlled by endogenous or synthetic inhibitors. Here, we demonstrate for the first time that loss of proteolytic activity of ADAM10 by either inhibition or loss of function mutations induces removal of the protease from the cell surface and the whole cell. This process is temperature dependent, restricted to mature ADAM10, and associated with an increased internalization, lysosomal degradation, and release of mature ADAM10 in extracellular vesicles. Recovery from this depletion requires de novo synthesis. Functionally, this is reflected by loss and recovery of ADAM10 substrate shedding. Finally, ADAM10 inhibition in mice reduces systemic ADAM10 levels in different tissues. Thus, ADAM10 activity is critically required for its surface expression in vitro and in vivo. These findings are crucial for development of therapeutic ADAM10 inhibition strategies and may showcase a novel, physiologically relevant mechanism of protease removal due to activity loss.
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http://dx.doi.org/10.1007/s00018-020-03507-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873107PMC
January 2021

The hyperpolarization-activated cyclic nucleotide-gated 4 channel as a potential anti-seizure drug target.

Br J Pharmacol 2020 Aug 17;177(16):3712-3729. Epub 2020 Jun 17.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.

Background And Purpose: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti-seizure strategy using pharmacological and genetic approaches.

Experimental Approach: The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model.

Key Results: EC18 (10 mg·kg ) and brain-specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant-mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant-mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV-HCN4 shRNA infected mouse cortical cultures.

Conclusions And Implications: These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti-seizure drugs that is likely to have a low side-effect liability in the CNS.
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http://dx.doi.org/10.1111/bph.15088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393203PMC
August 2020

Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells.

Br J Cancer 2020 May 25;122(11):1590-1603. Epub 2020 Mar 25.

Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505, Bratislava, Slovakia.

Background: Carbonic anhydrase IX (CA IX) is a hypoxia-induced enzyme regulating tumour pH and facilitating cell migration/invasion. It is primarily expressed as a transmembrane cell-surface protein, but its ectodomain can be shed by ADAM17 to extracellular space. This study aims to elucidate the impact of CA IX shedding on cancer cells.

Methods: We generated a non-shed CA IX mutant by deletion of amino acids 393-402 from the stalk region and studied its phenotypic effects compared to full-length, shedding-competent CA IX using a range of assays based on immunodetection, confocal microscopy, in vitro real-time cell monitoring and in vivo tumour cell inoculation using xenografted NMRI and C57BL/6J female mice.

Results: We demonstrated that the impairment of shedding does not alter the ability of CA IX to bind ADAM17, internalise, form oligomers and regulate pH, but induces cancer-promoting changes in extracellular proteome. Moreover, it affects intrinsic properties of cells expressing the non-shed variant, in terms of their increased ability to migrate, generate primary tumours and form metastatic lesions in lungs.

Conclusions: Our results show that the ectodomain shedding controls pro-tumorigenic and pro-metastatic roles of the cell-associated CA IX and suggest that this phenomenon should be considered when developing CA IX-targeted therapeutic strategies.
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http://dx.doi.org/10.1038/s41416-020-0804-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250822PMC
May 2020

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium.

Int J Mol Sci 2020 Feb 28;21(5). Epub 2020 Feb 28.

Institute of Anatomy and Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstraße 9, D-91054 Erlangen, Germany.

Calcium ions are vital for maintaining the physiological and biochemical processes inside cells. The central nervous system (CNS) is particularly dependent on calcium homeostasis and its dysregulation has been associated with several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD), as well as with multiple sclerosis (MS). Hence, the modulation of calcium influx into the cells and the targeting of calcium-mediated signaling pathways may present a promising therapeutic approach for these diseases. This review provides an overview on calcium channels in neurons and glial cells. Special emphasis is put on MS, a chronic autoimmune disease of the CNS. While the initial relapsing-remitting stage of MS can be treated effectively with immune modulatory and immunosuppressive drugs, the subsequent progressive stage has remained largely untreatable. Here we summarize several approaches that have been and are currently being tested for their neuroprotective capacities in MS and we discuss which role calcium could play in this regard.
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http://dx.doi.org/10.3390/ijms21051663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084497PMC
February 2020

Investigation of Peritectic Solidification Morphologies by Using the Binary Organic Model System TRIS-NPG.

Materials (Basel) 2020 Feb 21;13(4). Epub 2020 Feb 21.

Department of Metallurgy, Chair for Simulation and Modelling Metallurgical Processes, Montanuniversitaet Leoben, 8700 Leoben, Austria.

Under pure diffusive growth conditions, layered peritectic solidification is possible. In reality, the competitive growth of the primary α-phase and the peritectic β-phase revealed some complex peritectic solidification morphologies due to thermo-solutal convection. The binary organic components Tris-(hydroxylmenthyl) aminomethane-(Neopentylglycol) were used as a model system for metal-like solidification. The transparency of the high-temperature non-faceted phases allows for the studying of the dynamic of the solid/liquid interface that lead to peritectic solidification morphologies. Investigations were carried out by using the Bridgman technic for process conditions where one or both phases solidify in a non-planar manner. Different growth conditions were observed, leeding to competitive peritectic growth morphologies. Additionally, the competitive growth was solved numerically to interpret the observed transparent solidification patterns.
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http://dx.doi.org/10.3390/ma13040966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078857PMC
February 2020

Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family.

Mediators Inflamm 2019 3;2019:1603131. Epub 2019 Nov 3.

Department of Neonatology, University Children's Hospital, Aachen, Germany.

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that -infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-X, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-X and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.
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http://dx.doi.org/10.1155/2019/1603131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012211PMC
July 2020

Noncanonical Ion Channel Behaviour in Pain.

Int J Mol Sci 2019 Sep 15;20(18). Epub 2019 Sep 15.

Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

Ion channels contribute fundamental properties to cell membranes. Although highly diverse in conductivity, structure, location, and function, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Primarily considering ion channels involved in the nociceptive system, this review covers more novel and less known features. Accordingly, we outline noncanonical operation of voltage-gated sodium, potassium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Noncanonical features discussed include properties as a memory for prior voltage and chemical exposure, alternative ion conduction pathways, cluster formation, and silent subunits. Complementary to this main focus, the intention is also to transfer knowledge between fields, which become inevitably more separate due to their size.
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http://dx.doi.org/10.3390/ijms20184572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770626PMC
September 2019

Status update on iRhom and ADAM17: It's still complicated.

Biochim Biophys Acta Mol Cell Res 2019 10 19;1866(10):1567-1583. Epub 2019 Jul 19.

Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany. Electronic address:

Several membrane-bound proteins with a single transmembrane domain are subjected to limited proteolysis at the cell surface. This cleavage leads to the release of their biologically active ectodomains, which can trigger different signalling pathways. In many cases, this ectodomain shedding is mediated by members of the family of a disintegrins and metalloproteinases (ADAMs). ADAM17 in particular is responsible for the cleavage of several proinflammatory mediators, growth factors, receptors and adhesion molecules. Due to its direct involvement in the release of these signalling molecules, ADAM17 can be positively and negatively involved in various physiological processes as well as in inflammatory, fibrotic and malignant pathologies. This central role of ADAM17 in a variety of processes requires strict multi-level regulation, including phosphorylation, various conformational changes and endogenous inhibitors. Recent research has shown that an early, crucial control mechanism is interaction with certain adapter proteins identified as iRhom1 and iRhom2, which are pseudoproteases of the rhomboid superfamily. Thus, iRhoms have also a decisive influence on physiological and pathophysiological signalling processes regulated by ADAM17. Their characteristic gene expression profiles, the specific consequences of gene knockouts and finally the occurrence of disease-associated mutations suggest that iRhom1 and iRhom2 undergo different gene regulation in order to fulfil their function in different cell types and are therefore only partially redundant. Therefore, there is not only interest in ADAM17, but also in iRhoms as therapeutic targets. However, to exploit the therapeutic potential, the regulation of ADAM17 activity and in particular its interaction with iRhoms must be well understood.
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http://dx.doi.org/10.1016/j.bbamcr.2019.06.017DOI Listing
October 2019

The metalloproteinase ADAM15 is upregulated by shear stress and promotes survival of endothelial cells.

J Mol Cell Cardiol 2019 09 1;134:51-61. Epub 2019 Jul 1.

Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany. Electronic address:

Reduced shear stress resulting from disturbed blood flow can impair endothelial integrity and drive the development of vascular inflammatory lesions. Metalloproteinases of the ADAM family have been implicated in the regulation of cell survival and inflammatory responses. Here we investigate the mechanism and function of ADAM15 upregulation in primary flow cultured endothelial cells. Transcriptomic analysis indicated that within the ADAM family ADAM15 mRNA is most prominently upregulated (4-fold) when endothelial cells are exposed to physiologic shear stress. This induction was confirmed in venous, arterial and microvascular endothelial cells and is associated with increased presence of ADAM15 protein in the cell lysates (5.6-fold) and on the surface (3.1-fold). The ADAM15 promoter contains several consensus sites for the transcription factor KLF2 which is also upregulated by shear stress. Induction of endothelial KLF2 by simvastatin treatment is associated with ADAM15 upregulation (1.8-fold) which is suppressed by counteracting simvastatin with geranylgeranyl pyrophosphate. KLF2 overexpression promotes ADAM15 expression (2.1-fold) under static conditions whereas KLF2 siRNA knockdown prevents ADAM15 induction by shear stress. Functionally, ADAM15 promotes survival of endothelial cells challenged by growth factor depletion or TNF stimulation as shown by ADAM15 shRNA knockdown (1.6-fold). Exposure to shear stress increases endothelial survival while additional knockdown of ADAM15 reduces survival (6.7-fold) under flow conditions. Thus, physiologic shear stress resulting from laminar flow promotes KLF2 induced ADAM15 expression which contributes to endothelial survival. The absence of ADAM15 at low shear stress or static conditions may therefore lead to increased endothelial damage and promote vascular inflammation.
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http://dx.doi.org/10.1016/j.yjmcc.2019.06.017DOI Listing
September 2019

Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures.

JCI Insight 2019 05 2;4(9). Epub 2019 May 2.

Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually gated channels that are operated by voltage and by neurotransmitters via the cAMP system. cAMP-dependent HCN regulation has been proposed to play a key role in regulating circuit behavior in the thalamus. By analyzing a knockin mouse model (HCN2EA), in which binding of cAMP to HCN2 was abolished by 2 amino acid exchanges (R591E, T592A), we found that cAMP gating of HCN2 is essential for regulating the transition between the burst and tonic modes of firing in thalamic dorsal-lateral geniculate (dLGN) and ventrobasal (VB) nuclei. HCN2EA mice display impaired visual learning, generalized seizures of thalamic origin, and altered NREM sleep properties. VB-specific deletion of HCN2, but not of HCN4, also induced these generalized seizures of the absence type, corroborating a key role of HCN2 in this particular nucleus for controlling consciousness. Together, our data define distinct pathological phenotypes resulting from the loss of cAMP-mediated gating of a neuronal HCN channel.
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http://dx.doi.org/10.1172/jci.insight.126418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538325PMC
May 2019

Retrograde perfusion in isolated perfused mouse lungs-Feasibility and effects on cytokine levels and pulmonary oedema formation.

Basic Clin Pharmacol Toxicol 2019 Sep 21;125(3):279-288. Epub 2019 Apr 21.

Medical Faculty, Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.

Retrograde lung vascular perfusion can appear in high-risk surgeries. The present report is the first to study long-term retrograde perfusion of isolated perfused mouse lungs (IPLs) and to use the tyrosine kinase ephB4 and its ligand ephrinB2 as potential markers for acute lung injury. Mouse lungs were subjected to anterograde or retrograde perfusion with normal-pressure ventilation (NV) or high-pressure ventilation (=overventilation, OV) for 4 hours. Outcome parameters were cytokine, ephrinB2 and ephB4 levels in perfusate samples and bronchoalveolar lavage (BAL), and the wet-to-dry ratio. Anterograde perfusion was feasible for 4 hours, while lungs receiving retrograde perfusion presented considerable collapse rates. Retrograde perfusion resulted in an increased wet-to-dry ratio when combined with high-pressure ventilation; other physiological parameters were not affected. Cytokine levels in BAL and perfusate, as well as levels of soluble ephB4 in BAL were increased in OV, while soluble ephrinB2 BAL levels were increased in retrograde perfusion. BAL levels of ephrinB2 and ephB4 were also determined in vivo, including mice ventilated for 7 hours with normal-volume ventilation (NVV) or high-volume ventilation (HVV) with increased levels of ephB4 in HVV BAL compared to NVV. Retrograde perfusion in IPL is limited as a routine method to investigate effects due to collapse for yet unclear reasons. If successful, retrograde perfusion has an influence on pulmonary oedema formation. In BAL, ephrinB2 seems to be up-regulated by flow reversal, while ephB4 is a marker for acute lung injury.
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http://dx.doi.org/10.1111/bcpt.13236DOI Listing
September 2019

Elevated expression of the metalloproteinase ADAM8 associates with vascular diseases in mice and humans.

Atherosclerosis 2019 07 17;286:163-171. Epub 2019 Mar 17.

Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, UKS Bldg. 46, 66421, Homburg, Germany. Electronic address:

Background And Aims: Members of the family of a disintegrin and metalloproteinases (ADAMs) and their substrates have been previously shown to modulate the inflammatory response in cardiac diseases, but studies investigating the relevance of ADAM8 are still rare. Our aim is to provide evidence for the inflammatory dysregulation of ADAM8 in vascular diseases and its association with disease severity.

Methods: Western-type diet fed Apoe and Ldlr mice and artery ligation served as murine model for atherosclerosis and myocardial infarction, respectively. Human bypass grafts were used to study the association with coronary artery disease (CAD), with the simplified acute physiology score II (SAPS II) as a measure of postoperative organ dysfunction. Human primary vascular and blood cells were analyzed under basal and inflammatory conditions. mRNA levels were determined by RT-qPCR, ADAM8 protein levels by ELISA, immunohistochemistry or flow cytometry.

Results: ADAM8/ADAM8 expression is associated with atherosclerosis and CAD such as myocardial infarction in both mice and humans, especially in endothelial cells and leukocytes. We observed a strong in vivo and in vitro correlation of ADAM8 with the vascular disease markers VCAM-1, ICAM-1, TNF, IL-6, and CCL-2. Serum analysis revealed a significant elevation of soluble ADAM8 serum levels correlating with soluble CXCL16 levels and SAPS II.

Conclusions: We demonstrate a general association of ADAM8 with cardiovascular diseases in mice and humans predominantly acting in endothelial cells and leukocytes. The correlation with postoperative organ dysfunctions in CAD patients highlights the value of further studies investigating the specific function of ADAM8 in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.03.008DOI Listing
July 2019

Metalloproteinases TACE and MMP-9 Differentially Regulate Death Factors on Adult and Neonatal Monocytes After Infection with .

Int J Mol Sci 2019 Mar 20;20(6). Epub 2019 Mar 20.

Department of Neonatology, University Children's Hospital, Aachen 52074, Germany.

Cleaving ligands and receptors of the tumor necrosis factor (TNF) superfamily can critically regulate the induction of apoptosis. Matrix metalloproteinases (MMPs) such as MMP-9 and tumor necrosis factor-α-converting enzyme (TACE) have been shown to cleave CD95-Ligand (CD95L) and TNF/(TNF receptor-1) TNFR1 which induce phagocytosis induced cell death (PICD) in adult monocytes. This process is reduced in neonatal monocytes. Here we tested in vitro, whether infection mounts for activation of MMP-9 and TACE in monocytes and whether this process regulates PICD. The surface expression of TACE was most prominent on infected adult monocytes. In contrast, surface presentation of MMP-9 was highest on infected neonatal monocytes. Selective blocking of MMP-9 decreased CD95L secretion, while inhibition of TACE left CD95L secretion unaltered. Blocking of MMP-9 increased surface CD95L (memCD95L) expression on infected neonatal monocytes to levels comparable to infected adult monocytes. Moreover, MMP-9 inhibition raised PICD of infected neonatal monocytes to levels observed for infected adult monocytes. In contrast, TACE inhibition decreased PICD in infected monocytes. Addition of extracellular TNF effectively induced memCD95L presentation and PICD of adult monocytes and less of neonatal monocytes. MMP-9 activity is crucial for downregulating cell-contact dependent PICD in infected neonatal monocytes. By this mechanism, MMP-9 could contribute to reducing sustained inflammation in neonates.
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http://dx.doi.org/10.3390/ijms20061399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471605PMC
March 2019

The Hyperpolarization-Activated HCN4 Channel is Important for Proper Maintenance of Oscillatory Activity in the Thalamocortical System.

Cereb Cortex 2019 05;29(5):2291-2304

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Hyperpolarization-activated cation channels are involved, among other functions, in learning and memory, control of synaptic transmission and epileptogenesis. The importance of the HCN1 and HCN2 isoforms for brain function has been demonstrated, while the role of HCN4, the third major neuronal HCN subunit, is not known. Here we show that HCN4 is essential for oscillatory activity in the thalamocortical (TC) network. HCN4 is selectively expressed in various thalamic nuclei, excluding the thalamic reticular nucleus. HCN4-deficient TC neurons revealed a massive reduction of Ih and strongly reduced intrinsic burst firing, whereas the current was normal in cortical pyramidal neurons. In addition, evoked bursting in a thalamic slice preparation was strongly reduced in the mutant mice probes. HCN4-deficiency also significantly slowed down thalamic and cortical oscillations during active wakefulness. Taken together, these results establish that thalamic HCN4 channels are essential for the production of rhythmic intrathalamic oscillations and determine regular TC oscillatory activity during alert states.
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http://dx.doi.org/10.1093/cercor/bhz047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458902PMC
May 2019

ADAM10 mediates malignant pleural mesothelioma invasiveness.

Oncogene 2019 05 16;38(18):3521-3534. Epub 2019 Jan 16.

Laboratory of Tumour and Development Biology, GIGA-cancer, Liège University, Avenue Hippocrate 13, 4000, Liège, Belgium.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and mesothelioma development is very long, the local invasion of mesothelioma is very rapid leading to a mean survival of one year after diagnosis. ADAM10 (A Disintegrin And Metalloprotease) sheddase targets membrane-bound substrates and its overexpression is associated with progression in several cancers. However, nothing is known about ADAM10 implication in MPM. In this study, we demonstrated higher ADAM10 expression levels in human MPM as compared to control pleural samples and in human MPM cell line. This ADAM10 overexpression was also observed in murine MPM samples. Two mouse mesothelioma cell lines were used in this study including one primary cell line obtained by repeated asbestos fibre injections. We show, in vitro, that ADAM10 targeting through shRNA and pharmacological (GI254023X) approaches reduced drastically mesothelioma cell migration and invasion, as well as for human mesothelioma cells treated with siRNA targeting ADAM10. Moreover, ADAM10 downregulation in murine mesothelioma cells significantly impairs MPM progression in vivo after intrapleural cell injection. We also demonstrate that ADAM10 sheddase downregulation decreases the production of a soluble N-cadherin fragment through membrane N-cadherin, which stimulated mesothelioma cell migration. Taken together, we demonstrate that ADAM10 is overexpressed in MPM and takes part to MPM progression through the generation of N-cadherin fragment that stimulates mesothelioma cell migration. ADAM10 inhibition is worth considering as a therapeutic perspective in mesothelioma context.
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http://dx.doi.org/10.1038/s41388-018-0669-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756017PMC
May 2019

Novel role of APP cleavage by ADAM10 for breast cancer metastasis.

EBioMedicine 2018 12 29;38:5-6. Epub 2018 Nov 29.

Institute for Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2018.11.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306391PMC
December 2018

ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia.

J Biol Chem 2018 06 17;293(23):8912-8921. Epub 2018 Apr 17.

From the Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, EC1M 6BQ, United Kingdom,

ATP-sensitive potassium channels (K) contribute to membrane currents in many tissues, are responsive to intracellular metabolism, and open as ATP falls and ADP rises. K channels are widely distributed in tissues and are prominently expressed in the heart. They have generally been observed in ventricular tissue, but they are also expressed in the atria and conduction tissues. In this study, we focused on the contribution and role of the inwardly rectifying K channel subunit, Kir6.1, in the sinoatrial node (SAN). To develop a murine, conduction-specific Kir6.1 KO model, we selectively deleted Kir6.1 in the conduction system in adult mice (cKO). Electrophysiological data in single SAN cells indicated that Kir6.1 underlies a K current in a significant proportion of cells and influences early repolarization during pacemaking, resulting in prolonged cycle length. Implanted telemetry probes to measure heart rate and electrocardiographic characteristics revealed that the cKO mice have a slow heart rate, with episodes of sinus arrest in some mice. The PR interval (time between the onset of the P wave to the beginning of QRS complex) was increased, suggesting effects on the atrioventricular node. studies of whole heart or dissected heart regions disclosed impaired adaptive responses of the SAN to hypoxia, and this may have had long-term pathological consequences in the cKO mice. In conclusion, Kir6.1-containing K channels in the SAN have a role in excitability, heart rate control, and the electrophysiological adaptation of the SAN to hypoxia.
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http://dx.doi.org/10.1074/jbc.RA118.002775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995522PMC
June 2018

Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype.

Hum Mol Genet 2018 05;27(9):1533-1544

Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Cardiac calsequestrin (Casq2) associates with the ryanodine receptor 2 channel in the junctional sarcoplasmic reticulum to regulate Ca2+ release into the cytoplasm. Patients carrying mutations in CASQ2 display low resting heart rates under basal conditions and stress-induced polymorphic ventricular tachycardia (CPVT). In this study, we generate and characterize novel conditional deletion and conditional rescue mouse models to test the influence of developmental programs on the heart rate and CPVT phenotypes. We also compare the requirements for Casq2 function in the cardiac conduction system (CCS) and in working cardiomyocytes. Our study shows that the CPVT phenotype is dependent upon concurrent loss of Casq2 function in both the CCS and in working cardiomyocytes. Accordingly, restoration of Casq2 in only the CCS prevents CPVT. In addition, occurrence of CPVT is independent of the developmental history of Casq2-deficiency. In contrast, resting heart rate depends upon Casq2 gene activity only in the CCS and upon developmental history. Finally, our data support a model where low basal heart rate is a significant risk factor for CPVT.
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http://dx.doi.org/10.1093/hmg/ddy060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905597PMC
May 2018

The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice.

Mol Metab 2017 11 1;6(11):1339-1349. Epub 2017 Sep 1.

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Canada. Electronic address:

Objectives: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice.

Methods: The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1r). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo.

Results: Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1r mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1r mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart.

Conclusions: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.
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http://dx.doi.org/10.1016/j.molmet.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681270PMC
November 2017

Topological bootstrap: Fractionalization from Kondo coupling.

Sci Adv 2017 10 6;3(10):e1700729. Epub 2017 Oct 6.

Department of Physics, University of California Santa Barbara, CA 93106, USA.

Topologically ordered phases of matter can host fractionalized excitations known as "anyons," which obey neither Bose nor Fermi statistics. Despite forming the basis for topological quantum computation, experimental access to these exotic phases has been very limited. We present a new route toward realizing fractionalized topological phases by literally building on unfractionalized phases, which are much more easily realized experimentally. Our approach involves a Kondo lattice model in which a gapped electronic system of noninteracting fermions is coupled to local moments via the exchange interaction. Using general entanglement-based arguments and explicit lattice models, we show that gapped spin liquids can be induced in the spin system, and we demonstrate the power of this "topological bootstrap" by realizing chiral and spin liquids. This technique enables the realization of many long sought-after fractionalized phases of matter.
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http://dx.doi.org/10.1126/sciadv.1700729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630238PMC
October 2017

ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells.

Int J Cancer 2018 02 31;142(4):779-791. Epub 2017 Oct 31.

Department of Neurosurgery, Philipps University Marburg, Baldingerstr, Marburg, 35033, Germany.

Metastatic breast cancer affects long-term survival and is a major cause of cancer death for women worldwide. The Metalloprotease-Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB-231 breast cancer cells with ADAM8 knockdown (MB-231_shA8) and scramble control cells (MB-231_shCtrl) were analyzed for their capability to develop metastases. In vitro, formation of metastatic complexes in hanging drops is dependent on ADAM8 and blocked by ADAM8 inhibition. MB-231_shA8 in contrast to MB-231_shCtrl cells were impaired in transmigration through an endothelial and a reconstituted blood-brain barrier. Out of 23 MMP and 22 ADAM genes, only the MMP-9 gene was affected by ADAM8 knockdown in MB-231_shA8 cells. Following re-expression of wild-type ADAM8 in contrast to ADAM8 lacking the cytoplasmic domain in MB-231_shA8 cells caused increased levels of activated pERK1/2 and pCREB (S133) that were associated with elevated MMP-9 transcription. Application of ADAM8 and MMP-9 antibodies reduced transmigration of MB-231 cells suggesting that ADAM8 affects transmigration of breast cancer cells by MMP-9 regulation. ADAM8-dependent transmigration was confirmed in Hs578t cells overexpressing ADAM8. Moreover, transmigration of MB-231 and Hs578t cells was significantly reduced for cells treated with an antibody directed against P-selectin glycoprotein ligand (PSGL-1), a substrate of ADAM8. From these data we conclude that ADAM8 promotes early metastatic processes such as transendothelial migration by upregulation of MMP-9 and shedding of PSGL-1 from breast cancer cells.
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http://dx.doi.org/10.1002/ijc.31090DOI Listing
February 2018

Whole body and hematopoietic ADAM8 deficiency does not influence advanced atherosclerotic lesion development, despite its association with human plaque progression.

Sci Rep 2017 09 15;7(1):11670. Epub 2017 Sep 15.

Department of Pathology, CARIM, Maastricht University, Maastricht, The Netherlands.

Although A Disintegrin And Metalloproteinase 8 (ADAM8) is not crucial for tissue development and homeostasis, it has been implicated in various inflammatory diseases by regulating processes like immune cell recruitment and activation. ADAM8 expression has been associated with human atherosclerosis development and myocardial infarction, however a causal role of ADAM8 in atherosclerosis has not been investigated thus far. In this study, we examined the expression of ADAM8 in early and progressed human atherosclerotic lesions, in which ADAM8 was significantly upregulated in vulnerable lesions. In addition, ADAM8 expression was most prominent in the shoulder region of human atherosclerotic lesions, characterized by the abundance of foam cells. In mice, Adam8 was highly expressed in circulating neutrophils and in macrophages. Moreover, ADAM8 deficient mouse macrophages displayed reduced secretion of inflammatory mediators. Remarkably, however, neither hematopoietic nor whole-body ADAM8 deficiency in mice affected atherosclerotic lesion size. Additionally, except for an increase in granulocyte content in plaques of ADAM8 deficient mice, lesion morphology was unaffected. Taken together, whole body and hematopoietic ADAM8 does not contribute to advanced atherosclerotic plaque development, at least in female mice, although its expression might still be valuable as a diagnostic/prognostic biomarker to distinguish between stable and unstable lesions.
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http://dx.doi.org/10.1038/s41598-017-10549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601942PMC
September 2017

Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons.

Pain 2017 Oct;158(10):2012-2024

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Several studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. A near-complete lack of sensitization was observed in both mutant strains when peripheral inflammation was induced by an intradermal injection of 8br-cAMP. The lack of HCN2 as well as the inhibition of PKA eliminated the cAMP-mediated increase of calcium transients in dorsal root ganglion neurons. Facilitation of Ih via cAMP, a hallmark of the Ih current, was abolished in neurons without PKA activity. Collectively, these results show a significant contribution of both genes to inflammatory pain and suggest that PKA-dependent activation of HCN2 underlies cAMP-triggered neuronal sensitization.
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http://dx.doi.org/10.1097/j.pain.0000000000001005DOI Listing
October 2017

The metalloproteinase ADAM8 promotes leukocyte recruitment in vitro and in acute lung inflammation.

Am J Physiol Lung Cell Mol Physiol 2017 Sep 8;313(3):L602-L614. Epub 2017 Jun 8.

Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany; and

Alveolar leukocyte recruitment is a hallmark of acute lung inflammation and involves transmigration of leukocytes through endothelial and epithelial layers. The disintegrin and metalloproteinase (ADAM) 8 is expressed on human isolated leukocytic cells and can be further upregulated on cultured endothelial and epithelial cells by proinflammatory cytokines. By shRNA-mediated knockdown we show that leukocytic ADAM8 is required on monocytic THP-1 cells for chemokine-induced chemotaxis as well as transendothelial and transepithelial migration. Furthermore, ADAM8 promotes α-integrin upregulation and THP-1 cell adhesion to endothelial cells. On endothelial cells ADAM8 enhances transendothelial migration and increases cytokine-induced permeability. On epithelial cells the protease facilitates migration in a wound closure assay but does not affect transepithelial leukocyte migration. Blood leukocytes and bone marrow-derived macrophages (BMDM) from ADAM8-deficient mice show suppressed chemotactic response. Intranasal application of LPS to mice is accompanied with ADAM8 upregulation in the lung. In this model of acute lung inflammation ADAM8-deficient mice are protected against leukocyte infiltration. Finally, transfer experiments of BMDM in mice indicate that ADAM8 exerts a promigratory function predominantly on leukocytes. Our study provides in vitro and in vivo evidence that ADAM8 on leukocytes holds a proinflammatory function in acute lung inflammation by promoting alveolar leukocyte recruitment.
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http://dx.doi.org/10.1152/ajplung.00444.2016DOI Listing
September 2017