Jürgen Bernhagen

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SEEK ID: http://lmmeisd-2.srv.mwn.de/people/34

Location: Germany

ORCID: Not specified

Joined: 18th Dec 2024

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Published Datasets

This project serves as a centralized repository for omics datasets published by research groups within the SyNergy Cluster. It encompasses investigations such as proteomics and transcriptomics, which are further divided into individual studies led by SyNergy members. Each study is linked to relevant publications, assays and data files (with links to external repositories).

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Public web page: Not specified

Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa, Danio rerio

Unpublished Datasets

This project serves as a centralized repository for unpublished omics datasets from ongoing research led by SyNergy group leaders. It includes sample metadata and assay information for studies currently in progress, grouped under investigations such as proteomics and transcriptomics. The project aims to facilitate collaboration and data management within the cluster while maintaining confidentiality for unpublished work.

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Public web page: Not specified

Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa, Danio rerio

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LMU Klinikum

Country: Germany

City: Munich

Web page: https://www.lmu-klinikum.de/

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IKKβ binds NLRP3 providing a shortcut to inflammasome activation for rapid immune responses

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A rapid immune response to signals released from pathogens and injuries is critical for maintaining tissue integrity and restoring homeostasis. This response is largely mediated by the concerted action of pattern recognition receptors (PRRs). Such cooperativity has been described for Toll-like receptors (TLRs) and NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3), but the underlying molecular mechanisms remain incompletely understood. Inflammasomes are multi-protein complexes defined by ...

Submitter: Rainer Malik

Investigation: Proteomics (Published)

Assays: Untargeted Proteomics (mouse)

Snapshots: No snapshots

Created: 29th May 2024 at 11:28, Last updated: 15th Oct 2024 at 14:34

The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model

Published Datasets

In the context of studying the role of the COP9 signalosome (CSN) in neuroinflammation and ischemic neuronal damage, we studied the effect of the cullin NEDDylation state-modifying drugs MLN4924 and CSN5i-3 in BV2 microglial cells, an immortalized murine cell line featuring many of the characteristics of primary microglia. Owing to its potent inhibitory effect on the NEDDylation cascade, MLN4924 exhibits a CSN5-like anti-inflammatory activity. Csn5i-3 is a small molecule inhibitor that specifically ...

Submitter: Rainer Malik

Investigation: Proteomics (Published)

Assays: Shotgun proteomics (mouse)

Snapshots: No snapshots

Created: 9th Jul 2024 at 13:02, Last updated: 15th Oct 2024 at 11:22

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The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model.

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Abstract (Expand)

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While … the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity. Untargeted mass spectrometry-based proteomics revealed that MLN4924 and CSN5i-3 substantially alter the microglial proteome, including inflammation-related proteins. Applying these drugs and mimicking microglial and endothelial inflammation as well as ischemic neuronal stress by TNF and oxygen-glucose-deprivation/reoxygenation (OGD/RO) treatment, respectively, we could link CSN5/CSN-mediated cullin deNEDDylation to reduction of microglial inflammation, attenuated cerebral endothelial inflammation, improved barrier integrity, as well as protection from ischemic stress-induced neuronal cell death. Specifically, MLN4924 reduced phagocytic activity, motility, and inflammatory cytokine expression of microglial cells, and this was linked to inhibition of inflammation-induced NF-kappaB and Akt signaling. Inversely, Csn5 knockdown and CSN5i-3 increased NF-kappaB signaling. Moreover, MLN4924 abrogated TNF-induced NF-kappaB signaling in cerebral microvascular endothelial cells (hCMECs) and rescued hCMEC monolayers from OGD/RO-triggered barrier leakage, while CSN5i-3 exacerbated permeability. In an ex vivo organotypic brain slice model of ischemia/reperfusion stress, MLN4924 protected from neuronal death, while CSN5i-3 impaired neuronal survival. Neuronal damage was attributable to microglial activation and inflammatory cytokines, as indicated by microglial shape tracking and TNF-blocking experiments. Our results indicate a protective role of the CSN in neuroinflammation via brain-resident cell types involved in ischemic brain disease and implicate CSN activity-mimicking deNEDDylating drugs as potential therapeutics.

Authors: Y. Tian, J. Milic, L. S. Monasor, R. Chakraborty, S. Wang, Y. Yuan, Y. Asare, C. Behrends, S. Tahirovic, J. Bernhagen

Date Published: 19th Aug 2023

Publication Type: Journal

PubMed ID: 37597109

Citation: Cell Mol Life Sci. 2023 Aug 19;80(9):262. doi: 10.1007/s00018-023-04911-8.

Created: 8th Jul 2024 at 12:25

IKKβ binds NLRP3 providing a shortcut to inflammasome activation for rapid immune responses.

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Abstract

Not specified

Authors: Yaw Asare, Margarita Shnipova, Luka Živković, Christina Schlegl, Federica Tosato, Arailym Aronova, Markus Brandhofer, Laura Strohm, Nathalie Beaufort, Rainer Malik, Christian Weber, Jürgen Bernhagen, Martin Dichgans

Date Published: 19th Oct 2022

Publication Type: Journal

PubMed ID: 36257930

DOI: 10.1038/s41392-022-01189-3

Citation: Signal transduction and targeted therapy,7(1):355

Created: 15th Oct 2024 at 14:31

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.

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Abstract (Expand)

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 … in atherosclerosis and its clinical complications including stroke and myocardial infarction. Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6. Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation.

Authors: Yaw Asare, Thomas A Campbell-James, Yury Bokov, Lydia Luya Yu, Matthias Prestel, Omar El Bounkari, Stefan Roth, Remco T A Megens, Tobias Straub, Kyra Thomas, Guangyao Yan, Melanie Schneider, Natalie Ziesch, Steffen Tiedt, Carlos Silvestre-Roig, Quinte Braster, Yishu Huang, Manuela Schneider, Rainer Malik, Christof Haffner, Arthur Liesz, Oliver Soehnlein, Jürgen Bernhagen, Martin Dichgans

Date Published: 28th Aug 2020

Publication Type: Journal

PubMed ID: 32546048

DOI: 10.1161/CIRCRESAHA.120.316743

Citation: Circulation research,127(6):811-823

Created: 11th Oct 2024 at 13:13

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