Research Group A. Meisel

Regulators of cholinergic signaling in disorders of the central nervous system.
Winek K, Soreq H, Meisel A.
J Neurochem. 2021 Feb 26. doi: 10.1111/jnc.15332. Epub ahead of print.
PMID: 33638173.

Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade.
Winek K, Lobentanzer S, Nadorp B, Dubnov S, Dames C, Jagdmann S, Moshitzky G, Hotter B, Meisel C, Greenberg DS, Shifman S, Klein J, Shenhar-Tsarfaty S, Meisel A, Soreq H.
Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32606-32616. doi: 10.1073/pnas.2013542117. Epub 2020 Dec 7.
PMID: 33288717; PMCID: PMC7768686.

Interaction of microglia with infiltrating immune cells in the different phases of stroke.
Berchtold D, Priller J, Meisel C, Meisel A.
Brain Pathol. 2020 Nov;30(6):1208-1218. doi: 10.1111/bpa.12911. Epub 2020 Nov 2.
PMID: 33058417.

CD4+ T cells promote delayed B cell responses in the ischemic brain after experimental stroke.
Weitbrecht L, Berchtold D, Zhang T, Jagdmann S, Dames C, Winek K, Meisel C, Meisel A.
Brain Behav Immun. 2021 Jan;91:601-614. doi: 10.1016/j.bbi.2020.09.029. Epub 2020 Sep 28.
PMID: 33002634.

Infection as a Stroke Risk Factor and Determinant of Outcome After Stroke.
Elkind MSV, Boehme AK, Smith CJ, Meisel A, Buckwalter MS.
Stroke. 2020 Oct;51(10):3156-3168. doi: 10.1161/STROKEAHA.120.030429. Epub 2020 Sep 8.
PMID: 32897811; PMCID: PMC7530056.

Inflammatory and stress markers predicting pneumonia, outcome, and etiology in patients with stroke: Biomarkers for predicting pneumonia, functional outcome, and death after stroke.
Hotter B, Hoffmann S, Ulm L, Montaner J, Bustamante A, Meisel C, Meisel A.
Neurol Neuroimmunol Neuroinflamm. 2020 Feb 25;7(3):e692. doi: 10.1212/NXI.0000000000000692.
PMID: 32098866; PMCID: PMC7051196.

Identifying unmet needs in long-term stroke care using in-depth assessment and the Post-Stroke Checklist - The Managing Aftercare for Stroke (MAS-I) study.
Hotter B, Padberg I, Liebenau A, Knispel P, Heel S, Steube D, Wissel J, Wellwood I, Meisel A.
Eur Stroke J. 2018 Sep;3(3):237-245. doi: 10.1177/2396987318771174. Epub 2018 Apr 19. Erratum in: Eur Stroke J. 2019 Dec;4(4):NP2-NP4.
PMID: 31008354; PMCID: PMC6453198.

Stroke-induced immunodepression and dysphagia independently predict stroke-associated pneumonia - The PREDICT study.
Hoffmann S, Harms H, Ulm L, Nabavi DG, Mackert BM, Schmehl I, Jungehulsing GJ, Montaner J, Bustamante A, Hermans M, Hamilton F, Göhler J, Malzahn U, Malsch C, Heuschmann PU, Meisel C, Meisel A; PREDICT Investigators.
J Cereb Blood Flow Metab. 2017 Dec;37(12):3671-3682. doi: 10.1177/0271678X16671964. Epub 2016 Oct 14.
PMID: 27733675; PMCID: PMC5718319.

Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke.
Engel O, Akyüz L, da Costa Goncalves AC, Winek K, Dames C, Thielke M, Herold S, Böttcher C, Priller J, Volk HD, Dirnagl U, Meisel C, Meisel A.
Stroke. 2015 Nov;46(11):3232-40. doi: 10.1161/STROKEAHA.115.008989.
PMID:26451017

Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke.
Römer C, Engel O, Winek K, Hochmeister S, Zhang T, Royl G, Klehmet J, Dirnagl U, Meisel C, Meisel A.
J Neurosci. 2015 May 20;35(20):7777-94. doi: 10.1523/JNEUROSCI.1532-14.2015.
PMID:25995466

Stroke impairs the normally well-coordinated interplay between the nervous and immune systems, leading to the development of pneumonia in the acute and promoting the development of dementia in the chronic course. Stroke-associated pneumonia and post-stroke dementia are among the most common and important complications after stroke. Effective strategies to identify and treat stroke patients at high risk for pneumonia or dementia might significantly improve long-term outcome after stroke.

Stroke associated Pneumonia

The acute course of stroke is often complicated by pneumonia, which constitutes a leading cause of stroke mortality and morbidity. Most clinicians assume that post-stroke pneumonia is caused by aspiration due to dysphagia. Aspiration alone, however, cannot explain the high incidence of pneumonia in acute stroke. Although, pneumonia is the most frequent severe complication in the acute state of stroke, measures to manage this harmful complication have not improved over the past decades, and pneumonia still remains a serious problem in current clinical practice. Moreover, clinical trials demonstrated that preventive antibiotic therapy fails to reduce the incidence of pneumonia and improve outcome. In our research, we challenge current concepts of stroke-associated pneumonia. We have previously characterized a CNS injury-induced immunodepression syndrome,  which provides a molecular explanation for the high incidence of infectious complications in stroke patients. Stroke leads to an overactivation of neurohumoral stress pathways and subsequent downregulation of peripheral immune responses, which also includes the lung. In ongoing experiments we investigate the influence of stroke on the function and structure of the respiratory tracheal epithelium experimentally in our stroke models as well as in the clinical MUCINS study (Mucociliary Clearance in Stroke). We explore novel therapeutic strategies of pre-activating the pulmonary immunity to prevent bacterial infections in our experimental stroke models. In our clinical studies, we aim to establish new diagnostic markers that identify patients at risk for post-stroke pneumonia.

Post-Stroke Cognitive Decline

Vascular dementia and post-stroke cognitive decline are a further common complication after stroke resulting in an enormous individual and socioeconomic burden. Recent findings from experimental stroke suggest that the delayed post-stroke cognitive decline might be at least partially caused by B cell-mediated mechanisms. Importantly, post-stroke pneumonia might boost long-term autoreactive, CNS-specific immune responses, which are considered to be involved in secondary damage of the injured brain and development of post-stroke cognitive decline. We have previously demonstrated that autoreactive T and B cell mediated mechanisms are involved in poor outcome after experimental stroke. In particular, autoantibody secreting B cells in the ischemic brain have been linked to the occurrence of post-stroke dementia. Within the Stroke-IMPaCT network funded by the Leducq Foundation we are investigating how stroke-associated pneumonia exacerbates post-stroke cognitive decline. As part of the NeuroMac (TRR167) network funded by the German Research Foundation, we are currently investigating post-stroke B cell responses and their interaction with myeloid cells and T lymphocytes in the ischemic brain. In addition to the studies in our experimental model, we aim to prove our experimental findings in the BLISS (B-Lymphocyte Infiltration in Stroke Survivors) study using post-mortem brain tissues of stroke patients.

Within the framework of our post-stroke pneumonia and dementia projects we are interested in the following related projects.  

Role of small RNA molecules in dysregulation of immune homeostasis after stroke

The investigation of the regulatory function of small RNAs for the cholinergic arm of the autonomic nervous system and the importance for the immune system in stroke patients is the subject of an international collaborative project with Hermona Soreq (Hebrew University of Jerusalem) funded by the Einstein Foundation Berlin. In the project, we are investigating the role of two small RNA subtypes - microRNA and transfer RNA fragments (tRNA fragments). In particular, tRNA fragments, previously considered to be merely waste products of amino acid-transporting tRNAs, play an important role in gene regulation of immune cells. Our studies suggest very different functions of the two small RNA species for immune regulation. Indeed, levels of microRNA molecules decrease while tRNA fragments increase, with tRNA fragments in monocytes taking a central role in the immune response after stroke. This "changing of the guard" for cholinergic gene regulation in monocytes modulates immunity after stroke and likely plays a fundamental role in immune homeostasis. In the long term, we aim at establishing tRNA fragments as diagnostic biomarkers and therapeutic targets. We postulate that small RNAs can be used both to determine individual immune profiles and for therapeutic immunomodulation to better treat post-stroke complications.

Role of gut microbiota in modulating immunity after ischemic stroke

Stroke-induced changes in the gut microbiota influence neurological outcome after stroke. Immunological and metabolic mechanisms play a role here, which we are investigating in the context of our above interests in our experimental stroke model and in clinical studies. In a subproject we are investigating stroke-induced immunological changes in so-called "wildling" mice. These animals are conventional laboratory mice born with the natural microbiota of wild mice. Underlying these experiments is the hypothesis that the natural microbiome has an effect on outcome. If the hypothesis can be confirmed, we will use this approach to improve the transferability of our experimental studies thereby increasing the chances of success of our bench-to-bedside-to-bench approach.

MAS – Managing Aftercare for Stroke

In contrast to acute and rehabilitative stroke care, stroke aftercare is not very standardized. The MAS project constitutes of 3 phases and aims at developing a stroke aftercare concept. This observational study is designed to evaluate remaining deficits and needs of community-dwelling patients who suffered a stroke months and years ago. The study framework aims to develop an individualized complex and multidisciplinary intervention program to improve health-related quality of life for stroke patients. The patient-centered comprehensive care approach encompass a diagnostic step-by-step procedure with screening and, if necessary, further examination, which leads to a standardized therapy plan in consultation with the affected person, which must be adapted accordingly in the long-term course. In terms of content, both internistic domains (management of risk factors) and genuinely neurological domains (spasticity, cognitive deficits, etc.) were taken into account. Special challenges for this concept are the cross- and intra-sectoral communication between the professionals in the health care system as well as with the patients and relatives.

More information/project description
 

NAVICARE – patient-oriented health care research

NAVICARE creates a regional, active network for patient-oriented health care research under the project management of the Institute of Public Health.

More information/project description

• Claudia Dames, PhD
• PD Benjamin Hotter, MD
• Daniel Berchtold (PhD student)
• Luis Weitbrecht (MD/PhD student)
• Carla Dusemund (MD student)
• Claudia Muselmann (technical assistant)
• Sabine Kolodziej (technical assistant)
• Dike Remstedt (study coordinator)
   
• Christian Meisel, MD PhD (Institute for  Medical Immunology; Head Immunology, Labor Berlin GmbH)

• Wolfgang Kummer, Gießen
• Josef Priller, Munich
• Marco Prinz, Freiburg
   
• Stuart Allan, Manchester, UK
• Josef Anrather, New York, USA
• Marion Buckwalter, Stanford, USA
• Barry McColl, Manchester, UK
• Kristian Doyle, Tucson, USA
• Joan Montaner, Barcelona, Spain
• Maria Moro, Madrid, Spain
• Craig J. Smith, Manchester, UK
• Hermona Soreq, Jerusalem, Israel
   

Charité – Universitätsmedizin Berlin

• Falk Hiepe
• Helena Radburch
• Jens Rückert
• Werner Stenzel
• Martin Witzenrath

Einstein Foundation Berlin
A-2017-406, Role of microRNAs in post-stroke dysregulation and homeostasis of brain-body communication. 1/2019-12/2021

Foundation Leducq Transatlantic Networks of Excellence
19-CVD01,  "Stroke IMPaCT – Immune Mediated Pathways and Cognitive Trajectory", 01/2020-12/2024

German Research Foundation
DFG, SFB/TR167 "NeuroMac – Development, function and potential of myeloid cells in the central nervous system" TP B12: "Dissecting the crosstalk between myeloid cells, pericytes and lymphocytes for autoimmune-mediated mechanisms underlying post-stroke cognitive decline", 01/2021-12/2024