Filter and export

Publications

What is a Publication?
4 Publications matching the given criteria: (Clear all filters)
Author: Martin Dichgans4
Innate immune memory after brain injury drives inflammatory cardiac dysfunction.

Abstract (Expand)

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a … common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.

Authors: Alba Simats, Sijia Zhang, Denise Messerer, Faye Chong, Sude Beşkardeş, Aparna Sharma Chivukula, Jiayu Cao, Simon Besson-Girard, Felipe A Montellano, Caroline Morbach, Olga Carofiglio, Alessio Ricci, Stefan Roth, Gemma Llovera, Rashween Singh, Yiming Chen, Severin Filser, Nikolaus Plesnila, Christian Braun, Hannah Spitzer, Özgün Gökçe, Martin Dichgans, Peter U Heuschmann, Kinta Hatakeyama, Eduardo Beltrán, Sebastian Clauss, Boyan Bonev, Christian Schulz, Arthur Liesz

Date Published: 22nd Jul 2024

Publication Type: Journal

Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex.

Abstract (Expand)

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A … holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combine spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured male murine cerebral cortex, and identify specific states of different glial cells contributing to this signature. Interestingly, distinct glial cells share a large fraction of injury-regulated genes, including inflammatory programs downstream of the innate immune-associated pathways Cxcr3 and Tlr1/2. Systemic manipulation of these pathways decreases the reactivity state of glial cells associated with poor regeneration. The functional relevance of the discovered shared signature of glial cells highlights the importance of our resource enabling comprehensive analysis of early events after brain injury.

Authors: Christina Koupourtidou, Veronika Schwarz, Hananeh Aliee, Simon Frerich, Judith Fischer-Sternjak, Riccardo Bocchi, Tatiana Simon-Ebert, Xianshu Bai, Swetlana Sirko, Frank Kirchhoff, Martin Dichgans, Magdalena Götz, Fabian J Theis, Jovica Ninkovic

Date Published: 3rd Apr 2024

Publication Type: Journal

Distinct molecular profiles of skull bone marrow in health and neurological disorders.

Abstract (Expand)

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that … the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.

Authors: Zeynep Ilgin Kolabas, Louis B Kuemmerle, Robert Perneczky, Benjamin Förstera, Selin Ulukaya, Mayar Ali, Saketh Kapoor, Laura M Bartos, Maren Büttner, Ozum Sehnaz Caliskan, Zhouyi Rong, Hongcheng Mai, Luciano Höher, Denise Jeridi, Muge Molbay, Igor Khalin, Ioannis K Deligiannis, Moritz Negwer, Kenny Roberts, Alba Simats, Olga Carofiglio, Mihail I Todorov, Izabela Horvath, Furkan Ozturk, Selina Hummel, Gloria Biechele, Artem Zatcepin, Marcus Unterrainer, Johannes Gnörich, Jay Roodselaar, Joshua Shrouder, Pardis Khosravani, Benjamin Tast, Lisa Richter, Laura Díaz-Marugán, Doris Kaltenecker, Laurin Lux, Ying Chen, Shan Zhao, Boris-Stephan Rauchmann, Michael Sterr, Ines Kunze, Karen Stanic, Vanessa W Y Kan, Simon Besson-Girard, Sabrina Katzdobler, Carla Palleis, Julia Schädler, Johannes C Paetzold, Sabine Liebscher, Anja E Hauser, Özgün Gökçe, Heiko Lickert, Hanno Steinke, Corinne Benakis, Christian Braun, Celia P Martinez-Jimenez, Katharina Buerger, Nathalie L Albert, Günter Höglinger, Johannes Levin, Christian Haass, Anna Kopczak, Martin Dichgans, Joachim Havla, Tania Kümpfel, Martin Kerschensteiner, Martina Schifferer, Mikael Simons, Arthur Liesz, Natalie Krahmer, Omer A Bayraktar, Nicolai Franzmeier, Nikolaus Plesnila, Suheda Erener, Victor G Puelles, Claire Delbridge, Harsharan Singh Bhatia, Farida Hellal, Markus Elsner, Ingo Bechmann, Benjamin Ondruschka, Matthias Brendel, Fabian J Theis, Ali Ertürk

Date Published: 17th Aug 2023

Publication Type: Journal

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.

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

Powered by
 (v.1.15.0)
About FAIRDOM | About SyNergy (Munich Cluster for Systems Neurology) | Funding and Programmes | Credits
Copyright © 2008 - 2024 The University of Manchester and HITS gGmbH