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Investigating the effects of hypercholesterolemia on neutrophil-mediated thromboinflammation after cerebral ischemia

English title Investigating the effects of hypercholesterolemia on neutrophil-mediated thromboinflammation after cerebral ischemia
Applicant Klohs Jan
Number 179277
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biomedizinische Technik Universität und ETH Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pathophysiology
Start/End 01.07.2018 - 31.07.2021
Approved amount 435'656.00
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All Disciplines (2)

Discipline
Pathophysiology
Neurophysiology and Brain Research

Keywords (7)

cerebral ischemia; inflammation; hypercholesterolemia; photoacoustic imaging; magnetic resonance imaging; neutrophils; near-infrared fluorescence imaging

Lay Summary (German)

Lead
Hypercholesterinämie ist eine Lipidstoffwechselstörung und tritt häufig in Patienten mit ischämischem Schlaganfall auf, mit negativer Auswirkung auf den Verlauf der Erkrankung. Erhöhte Cholesterinwerte im Blut führen nachweislich zu immunologischen Veränderungen, aber wie sie sich die auf die zelluläre Immunreaktion und die Entwicklung des Schadens nach Schlaganfall im Gehirn auswirkt, ist weitestgehend unerforscht. Das Projekt untersucht in dem Zusammenhang den Einfluss der Hypercholesterinämie auf einen Hauptakteur der Immunantwort, den neutrophilen Granulozyt, im akuten Schlaganfall.
Lay summary

Inhalt und Ziel des Forschungsprojektes

In dem Projekt gehen wir der Fragestellung nach, ob die Hypercholesterinämie zu einem Anstieg der neutrophilen Granulozyten im Blut führt und ob dies zu einer Verstärkung des ischämischen Schadens und Verschlechterung der neurologischen Funktion nach einem Schlaganfall führt. Dies untersuchen wir sowohl in Schlaganfallpatienten als auch in einem experimentellen Modell der Erkrankung. Mit modernen bildgebende Verfahren untersuchen wir die zugrundeliegenden Mechanismen. Dabei wollen wir erforschen, ob die Neutrophilen an der Blutgerinnung beteiligt sind und damit die Versorgung des Schadengebietes mit Blut verhindern. Zum anderen werden wir untersuchen, ob diese Zellen zur akuten Gefässschädigung beitragen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Der Schlaganfall stellt immer noch ein grosses gesundheitliches Problem dar, wo Behandlungsmöglichkeiten gering und mit Risiken verbunden sind. Das geförderte Projekt soll zu neuen Erkenntnissen über die krankhaften immunologischen Prozesse nach Schlaganfall führen und somit wesentlich zu einer verbesserten Diagnostik und Behandlung der Erkrankung beitragen.

Direct link to Lay Summary Last update: 04.04.2018

Responsible applicant and co-applicants

Employees

Name Institute

Project partner

Publications

Publication
Quantitative susceptibility mapping in ischemic stroke patients after successful recanalization
Probst Jasmin, Rohner Marco, Zahn Malin, Piccirelli Marco, Pangalu Athina, Luft Andreas, Deistung Andreas, Klohs Jan, Wegener Susanne (2021), Quantitative susceptibility mapping in ischemic stroke patients after successful recanalization, in Scientific Reports, 11(1), 16038-16038.
Adeno-Associated Virus-Mediated Gain-of-Function mPCSK9 Expression in the Mouse Induces Hypercholesterolemia, Monocytosis, Neutrophilia, and a Hypercoagulative State
Louloudis Georgios, Ambrosini Samuele, Paneni Francesco, Camici Giovanni G., Benke Dietmar, Klohs Jan (2021), Adeno-Associated Virus-Mediated Gain-of-Function mPCSK9 Expression in the Mouse Induces Hypercholesterolemia, Monocytosis, Neutrophilia, and a Hypercoagulative State, in Frontiers in Cardiovascular Medicine, 8, 1.
In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice
Ni Ruiqing, Villois Alessia, Dean-Ben Xose Luis, Chen Zhenyue, Vaas Markus, Stavrakis Stavros, Shi Gloria, deMello Andrew, Ran Chongzhao, Razansky Daniel, Arosio Paolo, Klohs Jan (2021), In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice, in Photoacoustics, 23, 100285-100285.
Investigation of the magnetic susceptibility properties of fresh and fixed mouse heart, liver, skeletal muscle and brain tissue
Klohs Jan, Hirt Ann M. (2021), Investigation of the magnetic susceptibility properties of fresh and fixed mouse heart, liver, skeletal muscle and brain tissue, in Physica Medica, 88, 37-44.
Diffusion Tensor Imaging Reveals Whole-Brain Microstructural Changes in the P301L Mouse Model of Tauopathy
Massalimova Aidana, Ni Ruiqing, Nitsch Roger M., Reisert Marco, von Elverfeldt Dominik, Klohs Jan (2021), Diffusion Tensor Imaging Reveals Whole-Brain Microstructural Changes in the P301L Mouse Model of Tauopathy, in Neurodegenerative Diseases, 1-12.
Multi-scale optoacoustic molecular imaging of brain diseases
Razansky Daniel, Klohs Jan, Ni Ruiqing (2021), Multi-scale optoacoustic molecular imaging of brain diseases, in European Journal of Nuclear Medicine and Molecular Imaging, 200.
Pigment Epithelium-Derived Factor Improves Paracellular Blood–Brain Barrier Integrity in the Normal and Ischemic Mouse Brain
Riabinska Arina, Zille Marietta, Terzi Menderes Yusuf, Cordell Ryan, Nieminen-Kelhä Melina, Klohs Jan, Piña Ana Luisa (2020), Pigment Epithelium-Derived Factor Improves Paracellular Blood–Brain Barrier Integrity in the Normal and Ischemic Mouse Brain, in Cellular and Molecular Neurobiology, 40(5), 751-764.
SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy
Ni Ruiqing, Zarb Yvette, Kuhn Gisela A., Müller Ralph, Yundung Yankey, Nitsch Roger M., Kulic Luka, Keller Annika, Klohs Jan (2020), SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy, in Magnetic Resonance Materials in Physics, Biology and Medicine.
An Integrated View on Vascular Dysfunction in Alzheimer’s Disease
Klohs Jan (2020), An Integrated View on Vascular Dysfunction in Alzheimer’s Disease, in Neurodegenerative Diseases, 19(3-4), 109-127.
Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response
Zarb Yvette, Weber-Stadlbauer Ulrike, Kirschenbaum Daniel, Kindler Diana Rita, Richetto Juliet, Keller Daniel, Rademakers Rosa, Dickson Dennis W, Pasch Andreas, Byzova Tatiana, Nahar Khayrun, Voigt Fabian F, Helmchen Fritjof, Boss Andreas, Aguzzi Adriano, Klohs Jan, Keller Annika (2019), Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response, in Brain, 142(4), 885-902.
fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis
Ni Ruiqing, Kindler Diana Rita, Waag Rebecca, Rouault Marie, Ravikumar Priyanka, Nitsch Roger, Rudin Markus, Camici Giovanni G., Liberale Luca, Kulic Luka, Klohs Jan (2019), fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis, in Frontiers in Aging Neuroscience, 11, 27.
ICAM-1null C57BL/6 Mice Are Not Protected from Experimental Ischemic Stroke
Enzmann Gaby U., Pavlidou Sofia, Vaas Markus, Klohs Jan, Engelhardt Britta (2018), ICAM-1null C57BL/6 Mice Are Not Protected from Experimental Ischemic Stroke, in Translational Stroke Research, 9(6), 608-621.
Targeting the extradomain A of fibronectin allows identification of vascular resistance to antiangiogenic therapy in experimental glioma
Acker Güliz, Piper Sophie Käthe, Datwyler Anna Lena, Broggini Thomas, Kremenetskaia Irina, Nieminen-Kelhä Melina, Lips Janet, Harms Ulrike, Mueller Susanne, Lättig-Tünnemann Gilla, Trachsel Eveline, Palumbo Alessandro, Neri Dario, Klohs Jan, Endres Matthias, Vajkoczy Peter, Harms Christoph, Czabanka Marcus (2018), Targeting the extradomain A of fibronectin allows identification of vascular resistance to antiangiogenic therapy in experimental glioma, in Oncotarget, 9(45), 27760-27772.
Cortical hypoperfusion and reduced cerebral metabolic rate of oxygen in the arcAβ mouse model of Alzheimer’s disease
Ni Ruiqing, Rudin Markus, Klohs Jan (2018), Cortical hypoperfusion and reduced cerebral metabolic rate of oxygen in the arcAβ mouse model of Alzheimer’s disease, in Photoacoustics, 10, 38-47.
Sirtuin 5 as a novel target to blunt blood–brain barrier damage induced by cerebral ischemia/reperfusion injury
Diaz-Cañestro Candela, Merlini Mario, Bonetti Nicole R., Liberale Luca, Wüst Patricia, Briand-Schumacher Sylvie, Klohs Jan, Costantino Sara, Miranda Melroy, Schoedon-Geiser Gabriele, Kullak-Ublick Gerd A., Akhmedov Alexander, Paneni Francesco, Beer Jürg H., Lüscher Thomas F., Camici Giovanni G. (2018), Sirtuin 5 as a novel target to blunt blood–brain barrier damage induced by cerebral ischemia/reperfusion injury, in International Journal of Cardiology, 260, 148-155.
Noninvasive detection of acute cerebral hypoxia and subsequent matrix-metalloproteinase activity in a mouse model of cerebral ischemia using multispectral-optoacoustic-tomography
Ni Ruiqing, Vaas Markus, Ren Wuwei, Klohs Jan (2018), Noninvasive detection of acute cerebral hypoxia and subsequent matrix-metalloproteinase activity in a mouse model of cerebral ischemia using multispectral-optoacoustic-tomography, in Neurophotonics, 5(01), 1-1.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ZNZ Symposium Poster High precision in vivo assessment of Alzheimer’s ß-amyloid deposits with multi-scale optical imaging - from single plaques to whole brain mapping 10.09.2020 virtual, Switzerland Klohs Jan;
ZNZ Symposium Poster Investigating the effects of hypercholesterolemia on neutrophil mediated thromboinflammation after cerebral ischemia 10.09.2020 virtual, Switzerland Louloudis Georgios; Klohs Jan;
21st International Vascular Biology Meeting Talk given at a conference Tau deposition is associated with intracranial calcification in the P301L mouse model of human tauopathy 09.09.2020 virtual, Switzerland Klohs Jan;
European Molecular Imaging Meeting EMIM 2019 Poster High resolution patterns of beta-amyloid deposition in the whole mouse brain revealed by non-invasive dynamic OA 25.08.2020 virtual, Switzerland Klohs Jan;
European Molecular Imaging Meeting EMIM 2019 Talk given at a conference Transcranial detection of amyloid-beta at single plaque resolution in vivo with large-field multifocal illumination fluorescence microscopy 25.08.2020 virtual, Switzerland Klohs Jan;
Susceptibility-weighted and phase MR imaging for detecting intracranial calcifications in the P301L mouse model of human tauopathy Talk given at a conference European Molecular Imaging Meeting EMIM 2019 25.08.2020 virtual, Switzerland Klohs Jan;
International Society for Magnetic Resonance in Medicine (ISMRM) 28th Annual Meeting & Exhibition Talk given at a conference Changes in quantitative magnetization transfer MR in the mouse brain after transient cerebral ischemia 08.08.2020 virtual, Switzerland Klohs Jan;
lzheimer's Association International Conference Poster Transcranial detection of amyloid-beta at single plaque resolution in vivo with large-field multifocal illumination fluorescence microscopy 27.07.2020 virtual, Switzerland Klohs Jan;
Alzheimer's Association International Conference Poster Transcranial detection of tauopathy in vivo in P301L mice with high-resolution large-field multifocal illumination fluorescence microscopy 27.07.2020 virtual, Switzerland Klohs Jan;
Alzheimer's Association International Conference Poster Volumetric multispectral optoacoustic tomography of beta-amyloid deposits in whole mouse brain 27.07.2020 virtual, Switzerland Klohs Jan;
Seminar Neuro-Glia-Vascular (NGV) Network Individual talk Coagulation factor XII deficiency mitigates vascular impairment in the arcAβ mouse model of amyloidosis 07.07.2020 virtual, Switzerland Klohs Jan;
European Molecular Imaging Meeting EMIM 2019 Talk given at a conference Contrast-enhanced MRI microangiography of cerebral collateralization after chronic hypoperfusion in the mouse 19.03.2020 Glasgow, Great Britain and Northern Ireland Klohs Jan;
Transcranial detection of amyloid-beta at single plaque resolution in vivo with large-field multifocal illumination fluorescence microscopy Poster Transcranial detection of amyloid-beta at single plaque resolution in vivo with large-field multifocal illumination fluorescence microscopy 22.02.2020 Bern, Switzerland Klohs Jan;
Optoacoustic imaging meeting 2019; University Hospital Essen Poster Non-invasive volumetric maping of amyloid pathology across the whole mouse brain by photoacoustic tomography 14.11.2019 Essen, Germany Klohs Jan;
Optoacoustic imaging meeting 2019; University Hospital Essen Talk given at a conference Deciphering the dynamics of cerebral ischemia and brain diseases using multi-modal imaging 14.11.2019 Essen, Germany Klohs Jan;
Brain regional calcifications link with tauopathy in P301L tau mice Talk given at a conference Society for Neuroscience 19.10.2019 Chicago, United States of America Klohs Jan;
seminar University of Texas Southwestern Individual talk Non-invasive imaging of the diseased brain: from microstructure to cellular events 09.10.2019 Dallas, United States of America Klohs Jan;
ZNZ Symposium Poster Investigating the effects of hypercholesterolemia on neutrophil-mediated thromboinflammation after cerebral ischemia 12.09.2019 Zurich, Germany Louloudis Georgios; Klohs Jan;
ZNZ Symposium Poster Hippocampal tauopathy relates to brain calcifications in the P301L mouse model of human tauopathy 12.09.2019 Zurich, Switzerland Klohs Jan;
ZNZ Symposium Poster Coagulation factor XII deficiency mitigates cognitive and vascular impairment in the arcAβ mouse model of cerebral amyloidosis 12.09.2019 Zurich, Switzerland Klohs Jan;
10th Annual Scientific Symposium, Ultrahigh Field Magnetic Resonance: Clinical Needs, Research Promises and Technical Solutions Talk given at a conference Deciphering the dynamics of cerebral ischemia and brain diseases using multiscale imaging 06.09.2019 Berlin, Germany Klohs Jan;
10th Annual scientific symposium. Ultrahigh field magnetic resonance: clinical needs, research promises and technical solutions Poster Comparison of susceptibility-weighted MRI and phase imaging and micro-computed tomography for detecting intracranial calcifications in the P301L mouse model of human tauopathy 06.09.2019 Berlin, Germany Klohs Jan;
15th conference on subarachnoid haemorrhage Poster 15th conference on subarachnoid haemorrhage 25.06.2019 Amsterdam, Netherlands Klohs Jan;
International Association for Dental Research Poster Accuracy of Photoacoustic and NanoCT: Pilot In-Vitro Study in Human-Teeth. 19.06.2019 Vancouver, Canada Klohs Jan;
27th Annual meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), Talk given at a conference Contrast-enhanced MRI microangiography of cerebral collateralization after chronic hypoperfusion in the mouse 11.05.2019 Montreal, Canada Klohs Jan;
FENS Brain conference “Understanding and targeting Alzheimer´s disease” Poster Non-invasive volumetric maping of amyloid pathology across the whole mouse brain by photoacoustic tomography 05.05.2019 FENS Brain conference “Understanding and targeting Alzheimer´s disease”, Denmark Klohs Jan;
The 14th International conference on Alzheimer`s & Parkinson`s disease (AD/PD 2019) Talk given at a conference Genetic deletion of the coagulation factor XII mitigates cerebral microbleed load in the arcAβ mouse model of cerebral amyloidosis 26.03.2019 Lisbon, Portugal Klohs Jan;
The 14th International conference on Alzheimer`s & Parkinson`s disease Poster Genetic deletion of the coagulation factor XII mitigates cognitive and vascular impairment in the arcAβ mouse model of cerebral amyloidosis 26.03.2019 Lisbon, Portugal Klohs Jan;
European Molecular Imaging Meeting EMIM 2019 Poster MRI characterization of degenerative changes remote from the lesion in a rat model of spinal cord injury 19.03.2019 Glasgow, Great Britain and Northern Ireland Klohs Jan;
European Molecular Imaging Meeting EMIM 2019 Poster 3D imaging of amyloid pathology by non-invasive photoacoustic tomography and light-sheet microscopy in a mouse model of Alzheimer`s disease. 19.03.2019 Glasgow, Great Britain and Northern Ireland Klohs Jan;
European Molecular Imaging Meeting EMIM 2019 Poster Functional MRI reveals mitigation of cerebrovascular dysfunction by bradykinin receptor inhibitor noscapine in a mouse model of cerebral amyloidosis 19.03.2019 Glasgow, Great Britain and Northern Ireland Klohs Jan;
UK Dementia Research Institute, Imperial college London Individual talk Novel imaging techniques to map pathological events in age-related brain diseases 28.02.2019 London, Great Britain and Northern Ireland Klohs Jan;
ERA-NET NEURON mid-term symposium Poster Ex vivo validation of SCI-related changes with hMRI and NODDI-DTI in the brain and cervical cord 21.01.2019 Bonn, Germany Klohs Jan;
Annual meeting of the biomedical photonics network (BMPN) Talk given at a conference Novel imaging techniques to map pathological events in age-related brain diseases 11.12.2018 St Gallen, Switzerland Klohs Jan;
Synapsis Forum 2018 Poster Highly sensitive microfluidic assays for the analysis of reactions and concentrations of diagnositc biomarkers in Alzheimer`s disease 12.11.2018 Gerzensee, Switzerland Klohs Jan;
Synapsis Forum 2018 Poster Non-invasive photoacoustic tomography of amyloid deposits in mouse models of Alzheimer`s disease 12.11.2018 Gerzensee, Switzerland Klohs Jan;
Synapsis Forum 2018 Poster Genetic deletion of the coagulation factor XII mitigates vascular dysfunction and cognitive dysfunction in the arcAbeta mouse model of cerebral amyloidosis 12.11.2018 Gerzensee, Switzerland Klohs Jan;
Seminar series Neuro-Glia-Vascular (NGV) Network Individual talk Optical imaging of inflammation in stroke models 22.10.2018 Zurich, Switzerland Louloudis Georgios; Klohs Jan;
10th International Symposium on Neuroprotection and Neurorepair Talk given at a conference Multispectral-optoacoustic-tomography imaging of acute cerebral hypoxia and upregulation of matrix-metalloproteinase activity in a mouse model of cerebral ischemia and reperfusion 09.10.2018 Radebeul, Germany Klohs Jan;
10th International Symposium on Neuroprotection and Neurorepair Poster Prominent vessels on quantitative susceptibility maps indicate microvascular pathology after experimental cerebral ischemia and reperfusion 09.10.2018 Radebeul, Germany Klohs Jan;
10th International Symposium on Neuroprotection and Neurorepair Poster Degeneration of muscles supplied by the external carotid artery in the intraluminal filament mouse model of middle cerebral artery occlusion 09.10.2018 Radebeul, Germany Klohs Jan;
ZNZ Symposium Poster Genetic deletion of the coagulation FXII mitigates cognitive and vascular impairment in the arcAβ mouse model of Alzheimer’s disease 13.09.2018 Zurich, Switzerland Klohs Jan;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Meet the researchers 2019 Synapsis foundation Alzheimer`s research Switzerland Talk 24.09.2019 Zurich, Switzerland Klohs Jan;


Associated projects

Number Title Start Funding scheme
136822 Molecular imaging of neutrophil protease-mediated blood-brain barrier impairment and thrombosis after cerebral ischemia 01.01.2012 Ambizione

Abstract

Therapeutic options in acute ischemic stroke are limited and rely solely on pharmacological and mechanical recanalization strategies within a short therapeutic window after stroke. Despite high recanalization rates clinical outcome in these patients is highly variable. In stroke patients, hypercholesterolemia (HC) is a highly prevalent co-morbidity which has been shown to negatively impact clinical outcome after ischemic stroke. However, the mechanisms by which HC affects the ischemic injury remain largely unknown.Experimental studies have shown that HC induces systemic immune changes. It increases the number of circulating leukocytes; triggers activation of monocytes and neutrophils, cytokine production, and release of coagulation factors. Neutrophils have a particularly important role in this immune response. HC increases neutrophil production, primes neutrophils and leads to an increase in superoxide production and degranulation. Given the importance of thromboinflammatory processes in mediating blood-brain barrier damage, hemorrhagic transformation and secondary microvascular thrombosis after stroke, priming of neutrophils in HC might constitute an important way in exacerbating ischemic brain and reperfusion injury, but experimental evidence is still lacking.We herein propose to test the hypotheses that HC induces neutrophilia and primes neutrophils, and that this condition exacerbates ischemic tissue injury and worsens neurological outcome following cerebral ischemia and reperfusion. We will verify these hypotheses in patients with ischemic stroke, and then use preclinical models of human disease and advanced imaging techniques to elucidate the mechanisms by which neutrophils affect ischemic tissue damage and outcome, with a focus on hemodynamic function and vascular integrity. Specifically, we will address:1. Does HC induce neutrophilia, primes neutrophils and is it linked to measures of the thromboinflammatory response in patients with ischemic stroke and mice with experimental stroke?2. Do neutrophil extracellular traps mediate secondary microvascular thrombosis and prevent tissue reperfusion?3. Does current pharmacological thrombolysis following cerebral ischemia under HC conditions aggravate impairment of the blood-brain barrier and hemorrhagic transformation by enhancing reactive oxygen species production and degranulation?This project will bring novel insight into the role of HC on the pathophysiology of stroke. We predict that there are differences in the neutrophil response and their downstream-mediated processes in stroke patients with HC, where immunomodulatory therapy might be required to ameliorate ischemic and reperfusion injury and to improve outcome in such patients.
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