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36 Publications visible to you, out of a total of 36
A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model

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AbstractMultiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we … conducted a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule α4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4+ T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4+ T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions.

Authors: Arek Kendirli, Clara de la Rosa, Katrin F. Lämmle, Klara Eglseer, Isabel J. Bauer, Vladyslav Kavaka, Stephan Winklmeier, La Zhuo, Christian Wichmann, Lisa Ann Gerdes, Tania Kümpfel, Klaus Dornmair, Eduardo Beltrán, Martin Kerschensteiner, Naoto Kawakami

Date Published: 14th Sep 2023

Publication Type: Journal Article

Spatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury

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Abstract Understanding the complexity of cellular function within a tissue necessitates the combination of multiple phenotypic readouts. Here, we developed a method that links spatially-resolved gene …ally-resolved gene expression of single cells with their ultrastructural morphology by integrating multiplexed error-robust fluorescence in situ hybridization (MERFISH) and large area volume electron microscopy (EM) on adjacent tissue sections. Using this method, we characterized in situ ultrastructural and transcriptional responses of glial cells and infiltrating T-cells after demyelinating brain injury in male mice. We identified a population of lipid-loaded “foamy” microglia located in the center of remyelinating lesion, as well as rare interferon-responsive microglia, oligodendrocytes, and astrocytes that co-localized with T-cells. We validated our findings using immunocytochemistry and lipid staining-coupled single-cell RNA sequencing. Finally, by integrating these datasets, we detected correlations between full-transcriptome gene expression and ultrastructural features of microglia. Our results offer an integrative view of the spatial, ultrastructural, and transcriptional reorganization of single cells after demyelinating brain injury.

Authors: Peter Androvic, Martina Schifferer, Katrin Perez Anderson, Ludovico Cantuti-Castelvetri, Hanyi Jiang, Hao Ji, Lu Liu, Garyfallia Gouna, Stefan A. Berghoff, Simon Besson-Girard, Johanna Knoferle, Mikael Simons, Ozgun Gokce

Date Published: 11th Jul 2023

Publication Type: Journal Article

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions

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Abstract Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). …le sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Authors: Yi-Heng Tai, Daniel Engels, Giuseppe Locatelli, Ioanna Emmanouilidis, Caroline Fecher, Delphine Theodorou, Stephan A. Müller, Simon Licht-Mayer, Mario Kreutzfeldt, Ingrid Wagner, Natalia Prudente de Mello, Sofia-Natsouko Gkotzamani, Laura Trovò, Arek Kendirli, Almir Aljović, Michael O. Breckwoldt, Ronald Naumann, Florence M. Bareyre, Fabiana Perocchi, Don Mahad, Doron Merkler, Stefan F. Lichtenthaler, Martin Kerschensteiner, Thomas Misgeld

Date Published: 10th Jul 2023

Publication Type: Journal Article

Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

Abstract (Expand)

Abstract Axonal degeneration determines the clinical outcome of multiple sclerosis and is thought to result from exposure of denuded axons to immune-mediated damage. Therefore, myelin is widely considered … widely considered to be a protective structure for axons in multiple sclerosis. Myelinated axons also depend on oligodendrocytes, which provide metabolic and structural support to the axonal compartment. Given that axonal pathology in multiple sclerosis is already visible at early disease stages, before overt demyelination, we reasoned that autoimmune inflammation may disrupt oligodendroglial support mechanisms and hence primarily affect axons insulated by myelin. Here, we studied axonal pathology as a function of myelination in human multiple sclerosis and mouse models of autoimmune encephalomyelitis with genetically altered myelination. We demonstrate that myelin ensheathment itself becomes detrimental for axonal survival and increases the risk of axons degenerating in an autoimmune environment. This challenges the view of myelin as a solely protective structure and suggests that axonal dependence on oligodendroglial support can become fatal when myelin is under inflammatory attack.

Authors: Erik Schäffner, Mar Bosch-Queralt, Julia M. Edgar, Maria Lehning, Judith Strauß, Niko Fleischer, Theresa Kungl, Peter Wieghofer, Stefan A. Berghoff, Tilo Reinert, Martin Krueger, Markus Morawski, Wiebke Möbius, Alonso Barrantes-Freer, Jens Stieler, Ting Sun, Gesine Saher, Markus H. Schwab, Christoph Wrede, Maximilian Frosch, Marco Prinz, Daniel S. Reich, Alexander Flügel, Christine Stadelmann, Robert Fledrich, Klaus-Armin Nave, Ruth M. Stassart

Date Published: 29th Jun 2023

Publication Type: Journal Article

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

Abstract (Expand)

Abstract The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing …s still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2,3 . As oligodendrocytes support axonal energy metabolism and neuronal health 4–7 , we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

Authors: Constanze Depp, Ting Sun, Andrew Octavian Sasmita, Lena Spieth, Stefan A. Berghoff, Taisiia Nazarenko, Katharina Overhoff, Agnes A. Steixner-Kumar, Swati Subramanian, Sahab Arinrad, Torben Ruhwedel, Wiebke Möbius, Sandra Göbbels, Gesine Saher, Hauke B. Werner, Alkmini Damkou, Silvia Zampar, Oliver Wirths, Maik Thalmann, Mikael Simons, Takashi Saito, Takaomi Saido, Dilja Krueger-Burg, Riki Kawaguchi, Michael Willem, Christian Haass, Daniel Geschwind, Hannelore Ehrenreich, Ruth Stassart, Klaus-Armin Nave

Date Published: 31st May 2023

Publication Type: Journal Article

T cells modulate the microglial response to brain ischemia

Abstract (Expand)

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small … number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism of how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations – with T H1 cells inducing a type I INF signaling in microglia and regulatory T cells (T REG ) cells promoting microglial genes associated with chemotaxis. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. Whereas microglia polarization by T cell subsets did not affect the acute development of the infarct volume, these findings substantiate the role of T cells in stroke by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions.

Authors: Corinne Benakis, Alba Simats, Sophie Tritschler, Steffanie Heindl, Simon Besson-Girard, Gemma Llovera, Kelsey Pinkham, Anna Kolz, Alessio Ricci, Fabian J Theis, Stefan Bittner, Özgün Gökce, Anneli Peters, Arthur Liesz

Date Published: 13th Dec 2022

Publication Type: Journal Article

CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging

Abstract (Expand)

AbstractA hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found … age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8+ T cells in aging white matter. In summary, we provide evidence that CD8+ T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

Authors: Tuğberk Kaya, Nicola Mattugini, Lu Liu, Hao Ji, Ludovico Cantuti-Castelvetri, Jianping Wu, Martina Schifferer, Janos Groh, Rudolf Martini, Simon Besson-Girard, Seiji Kaji, Arthur Liesz, Ozgun Gokce, Mikael Simons

Date Published: 24th Oct 2022

Publication Type: Journal Article

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