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1.
Proc Natl Acad Sci U S A ; 119(40): e2204509119, 2022 10 04.
Article in English | MEDLINE | ID: mdl-36161894

ABSTRACT

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.


Subject(s)
Azetidines , Benzyl Compounds , Multiple Sclerosis, Chronic Progressive , Oligodendroglia , Sphingosine-1-Phosphate Receptors , Sphingosine , Animals , Azetidines/pharmacology , Benzyl Compounds/pharmacology , Cuprizone , Disease Models, Animal , Homeodomain Proteins/genetics , Mice , Mice, Inbred C57BL , Multiple Sclerosis, Chronic Progressive/drug therapy , Oligodendroglia/drug effects , Sphingosine/pharmacology , Sphingosine/therapeutic use , Sphingosine-1-Phosphate Receptors/metabolism
2.
Int J Mol Sci ; 25(3)2024 Jan 24.
Article in English | MEDLINE | ID: mdl-38338724

ABSTRACT

Multiple sclerosis (MS) is an autoimmune and inflammatory disorder affecting the central nervous system whose cause is still largely unknown. Oligodendrocyte degeneration results in demyelination of axons, which can eventually be repaired by a mechanism called remyelination. Prevention of demyelination and the pharmacological support of remyelination are two promising strategies to ameliorate disease progression in MS patients. The cuprizone model is commonly employed to investigate oligodendrocyte degeneration mechanisms or to explore remyelination pathways. During the last decades, several different protocols have been applied, and all have their pros and cons. This article intends to offer guidance for conducting pre-clinical trials using the cuprizone model in mice, focusing on discovering new treatment approaches to prevent oligodendrocyte degeneration or enhance remyelination.


Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Remyelination , Humans , Mice , Animals , Cuprizone , Myelin Sheath/metabolism , Demyelinating Diseases/metabolism , Oligodendroglia/metabolism , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Mice, Inbred C57BL , Disease Models, Animal
3.
Glia ; 71(7): 1683-1698, 2023 07.
Article in English | MEDLINE | ID: mdl-36945189

ABSTRACT

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.


Subject(s)
Central Nervous System Diseases , Encephalomyelitis, Autoimmune, Experimental , Animals , Mice , Cuprizone/toxicity , Sulfates/adverse effects , Oligodendroglia/pathology , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/pathology , Corpus Callosum/pathology , Central Nervous System Diseases/pathology , Heparitin Sulfate/therapeutic use , Mice, Inbred C57BL , Disease Models, Animal , Myelin Sheath/pathology
4.
Clin Exp Immunol ; 214(1): 1-17, 2023 12 11.
Article in English | MEDLINE | ID: mdl-37410892

ABSTRACT

Multiple sclerosis (MS) is characterized by the chronic inflammatory destruction of myelinated axons in the central nervous system. Several ideas have been put forward to clarify the roles of the peripheral immune system and neurodegenerative events in such destruction. Yet, none of the resulting models appears to be consistent with all the experimental evidence. They also do not answer the question of why MS is exclusively seen in humans, how Epstein-Barr virus contributes to its development but does not immediately trigger it, and why optic neuritis is such a frequent early manifestation in MS. Here we describe a scenario for the development of MS that unifies existing experimental evidence as well as answers the above questions. We propose that all manifestations of MS are caused by a series of unfortunate events that usually unfold over a longer period of time after a primary EBV infection and involve periodic weakening of the blood-brain barrier, antibody-mediated CNS disturbances, accumulation of the oligodendrocyte stress protein αB-crystallin and self-sustaining inflammatory damage.


Subject(s)
Epstein-Barr Virus Infections , Multiple Sclerosis , Humans , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human , Central Nervous System , Blood-Brain Barrier/pathology
5.
Neuropathol Appl Neurobiol ; 49(1): e12851, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36181265

ABSTRACT

AIMS: Axonal injury in multiple sclerosis (MS) and experimental models is most frequently detected in acutely demyelinating lesions. We recently reported a compensatory neuronal response, where mitochondria move to the acutely demyelinated axon and increase the mitochondrial content following lysolecithin-induced demyelination. We termed this homeostatic phenomenon, which is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). The aim of this study is to determine whether ARMD is consistently evident in experimental demyelination and how its perturbation relates to axonal injury. METHODS: In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (cytochrome c oxidase or COX) of axons and related these to axonal injury in nine different experimental disease models. We used immunofluorescent histochemistry as well as sequential COX histochemistry followed by immunofluorescent labelling of mitochondria and axons. RESULTS: We found ARMD a consistent and robust phenomenon in all experimental disease models. The increase in mitochondrial content within demyelinated axons, however, was not always accompanied by a proportionate increase in complex IV activity, particularly in highly inflammatory models such as experimental autoimmune encephalomyelitis (EAE). Axonal complex IV activity inversely correlated with the extent of axonal injury in experimental disease models. CONCLUSIONS: Our findings indicate that ARMD is a consistent and prominent feature and emphasise the importance of complex IV activity in the context of ARMD, especially in autoimmune inflammatory demyelination, paving the way for the development of novel neuroprotective therapies.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Multiple Sclerosis/pathology , Axons/pathology , Encephalomyelitis, Autoimmune, Experimental/pathology , Neurons/pathology , Mitochondria/pathology
6.
Int J Mol Sci ; 24(22)2023 Nov 16.
Article in English | MEDLINE | ID: mdl-38003609

ABSTRACT

A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at both the molecular and histological levels. These aberrations are closely linked to dysfunction of oligodendrocytes and alterations in myelin structure, which may be pivotal factors contributing to the disconnection of brain regions and the resulting characteristic clinical impairments observed in these conditions. Astrocytes, which significantly outnumber neurons in the central nervous system by a five-to-one ratio, play indispensable roles in the development, maintenance, and overall well-being of neurons and oligodendrocytes. Consequently, they emerge as potential key players in the onset and progression of a myriad of neurological and psychiatric disorders. Furthermore, targeting astrocytes represents a promising avenue for therapeutic intervention in such disorders. To gain deeper insights into the functions of astrocytes in the context of myelin-related disorders, it is imperative to employ appropriate in vivo models that faithfully recapitulate specific aspects of complex human diseases in a reliable and reproducible manner. One such model is the cuprizone model, wherein metabolic dysfunction in oligodendrocytes initiates an early response involving microglia and astrocyte activation, culminating in multifocal demyelination. Remarkably, following the cessation of cuprizone intoxication, a spontaneous process of endogenous remyelination occurs. In this review article, we provide a historical overview of studies investigating the responses and putative functions of astrocytes in the cuprizone model. Following that, we list previously published works that illuminate various aspects of the biology and function of astrocytes in this multiple sclerosis model. Some of the studies are discussed in more detail in the context of astrocyte biology and pathology. Our objective is twofold: to provide an invaluable overview of this burgeoning field, and, more importantly, to inspire fellow researchers to embark on experimental investigations to elucidate the multifaceted functions of this pivotal glial cell subpopulation.


Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Humans , Animals , Mice , Cuprizone/toxicity , Demyelinating Diseases/metabolism , Astrocytes/metabolism , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Multiple Sclerosis/metabolism , Microglia/metabolism , Mice, Inbred C57BL , Disease Models, Animal
7.
Int J Mol Sci ; 24(12)2023 Jun 18.
Article in English | MEDLINE | ID: mdl-37373448

ABSTRACT

Renal transplantation is now the best treatment for end-stage renal failure. To avoid rejection and prolong graft function, organ recipients need immunosuppressive therapy. The immunosuppressive drugs used depends on many factors, including time since transplantation (induction or maintenance), aetiology of the disease, and/or condition of the graft. Immunosuppressive treatment needs to be personalised, and hospitals and clinics have differing protocols and preparations depending on experience. Renal transplant recipient maintenance treatment is mostly based on triple-drug therapy containing calcineurin inhibitors, corticosteroids, and antiproliferative drugs. In addition to the desired effect, the use of immunosuppressive drugs carries risks of certain side effects. Therefore, new immunosuppressive drugs and immunosuppressive protocols are being sought that exert fewer side effects, which could maximise efficacy and reduce toxicity and, in this way, reduce both morbidity and mortality, as well as increase opportunities to modify individual immunosuppression for renal recipients of all ages. The aim of the current review is to describe the classes of immunosuppressive drugs and their mode of action, which are divided by induction and maintenance treatment. An additional aspect of the current review is a description of immune system activity modulation by the drugs used in renal transplant recipients. Complications associated with the use of immunosuppressive drugs and other immunosuppressive treatment options used in kidney transplant recipients have also been described.


Subject(s)
Kidney Transplantation , Humans , Kidney Transplantation/methods , Graft Rejection/drug therapy , Graft Rejection/prevention & control , Immunosuppressive Agents/adverse effects , Immunosuppression Therapy/methods , Calcineurin Inhibitors/adverse effects
8.
Int J Mol Sci ; 24(13)2023 Jun 23.
Article in English | MEDLINE | ID: mdl-37445742

ABSTRACT

The Cuprizone mouse model is widely used in studies on de- and remyelination. In the hands of different experimenters, the Cuprizone concentrations that lead to comparable levels of demyelination differ considerably. The reasons for this variability are unknown. In this study, we tested whether different Cuprizone formulations from different vendors and manufacturers influenced Cuprizone-induced histopathological hallmarks. We intoxicated male C57BL/6 mice with six Cuprizone powders that differed in their manufacturer, vendor, and purity. After five weeks, we analyzed the body weight changes over the course of the experiment, as well as the demyelination, astrogliosis, microgliosis and axonal damage by histological LFB-PAS staining and immunohistochemical labelling of PLP, IBA1, GFAP and APP. All Cuprizone formulations induced demyelination, astrogliosis, microgliosis, axonal damage and a moderate drop in body weight at the beginning of the intoxication period. In a cumulative evaluation of all analyses, two Cuprizone formulations performed weaker than the other formulations. In conclusion, all tested formulations did work, but the choice of Cuprizone formulation may have been responsible for the considerable variability in the experimental outcomes.


Subject(s)
Cuprizone , Demyelinating Diseases , Male , Animals , Mice , Cuprizone/toxicity , Gliosis , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Mice, Inbred C57BL , Body Weight , Disease Models, Animal , Myelin Sheath/pathology
9.
Glia ; 70(11): 2188-2206, 2022 11.
Article in English | MEDLINE | ID: mdl-35856297

ABSTRACT

Multiple sclerosis (MS) is a central nervous system disease characterized by both degenerative and inflammatory processes. Various mediators are involved in the interplay of degeneration and innate immunity on one hand and peripheral adaptive immunity on the other hand. The secreted protein lipocalin 2 (LCN2) is an inflammatory modulator in a variety of pathologies. Although elevated intrathecal levels of LCN2 have been reported in MS patients, it's functional role is widely unknown. Here, we identified a subpopulation of astrocytes as a source of LCN2 in MS lesions and respective animal models. We investigated the functional role of LCN2 for both autoimmune and degenerative aspects in three MS mouse models including both wild type (WT) and Lcn2-/- mouse strains. While the experimental autoimmune encephalomyelitis (EAE) model reflects primary autoimmunity, the cuprizone model reflects selective oligodendrocyte loss and demyelination. In addition, we included a combinatory Cup/EAE model in which primary cytodegeneration is followed by inflammatory lesions within the forebrain. While in the EAE model, the disease outcome was comparable in between the two mouse strains, cuprizone intoxicated Lcn2-/- animals showed an increased loss of oligodendrocytes. In the Cup/EAE model, Lcn2-/- animals showed increased inflammation when compared to WT mice. Together, our results highlight LCN2 as a potentially protective molecule in MS lesion formation, which might be able to limit loss of oligodendrocytes immune-cell invasion. Despite these findings, it is not yet clear which glial cell phenotype (and to which extent) contributes to the observed neuroprotective effects, that is, microglia and/or astroglia or even endothelial cells in the brain.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Lipocalin-2/metabolism , Multiple Sclerosis , Animals , Cuprizone , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/metabolism , Endothelial Cells/metabolism , Lipocalin-2/genetics , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Oligodendroglia/metabolism , Prosencephalon/pathology
10.
Glia ; 70(6): 1170-1190, 2022 06.
Article in English | MEDLINE | ID: mdl-35246882

ABSTRACT

Microglia are the resident innate immune cells of the central nervous system (CNS) parenchyma. To determine the impact of microglia on disease development and progression in neurodegenerative and neuroinflammatory diseases, it is essential to distinguish microglia from peripheral macrophages/monocytes, which are eventually equally recruited. It has been suggested that transmembrane protein 119 (TMEM119) serves as a reliable microglia marker that discriminates resident microglia from blood-derived macrophages in the human and murine brain. Here, we investigated the validity of TMEM119 as a microglia marker in four in vivo models (cuprizone intoxication, experimental autoimmune encephalomyelitis (EAE), permanent filament middle cerebral artery occlusion (fMCAo), and intracerebral 6-hydroxydopamine (6-OHDA) injections) as well as post mortem multiple sclerosis (MS) brain tissues. In all applied animal models and post mortem MS tissues, we found increased densities of ionized calcium-binding adapter molecule 1+ (IBA1+ ) cells, paralleled by a significant decrease in TMEM119 expression. In addition, other cell types in peripheral tissues (i.e., follicular dendritic cells and brown adipose tissue) were also found to express TMEM119. In summary, this study demonstrates that TMEM119 is not exclusively expressed by microglia nor does it label all microglia, especially under cellular stress conditions. Since novel transgenic lines have been developed to label microglia using the TMEM119 promotor, downregulation of TMEM119 expression might interfere with the results and should, thus, be considered when working with these transgenic mouse models.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Microglia , Animals , Central Nervous System , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/metabolism , Macrophages/metabolism , Mice , Mice, Transgenic , Microglia/metabolism
11.
Eur Radiol ; 32(2): 1014-1023, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34463797

ABSTRACT

OBJECTIVES: Knowledge about cochlear duct length (CDL) may assist electrode choice in cochlear implantation (CI). However, no gold standard for clinical applicable estimation of CDL exists. The aim of this study is (1) to determine the most reliable radiological imaging method and imaging processing software for measuring CDL from clinical routine imaging and (2) to accurately predict the insertion depth of the CI electrode. METHODS: Twenty human temporal bones were examined using different sectional imaging techniques (high-resolution computed tomography [HRCT] and cone beam computed tomography [CBCT]). CDL was measured using three methods: length estimation using (1) a dedicated preclinical 3D reconstruction software, (2) the established A-value method, and (3) a clinically approved otosurgical planning software. Temporal bones were implanted with a 31.5-mm CI electrode and measurements were compared to a reference based on the CI electrode insertion angle measured by radiographs in Stenvers projection (CDLreference). RESULTS: A mean cochlear coverage of 74% (SD 7.4%) was found. The CDLreference showed significant differences to each other method (p < 0.001). The strongest correlation to the CDLreference was found for the otosurgical planning software-based method obtained from HRCT (CDLSW-HRCT; r = 0.87, p < 0.001) and from CBCT (CDLSW-CBCT; r = 0.76, p < 0.001). Overall, CDL was underestimated by each applied method. The inter-rater reliability was fair for the CDL estimation based on 3D reconstruction from CBCT (CDL3D-CBCT; intra-class correlation coefficient [ICC] = 0.43), good for CDL estimation based on 3D reconstruction from HRCT (CDL3D-HRCT; ICC = 0.71), poor for CDL estimation based on the A-value method from HRCT (CDLA-HRCT; ICC = 0.29), and excellent for CDL estimation based on the A-value method from CBCT (CDLA-CBCT; ICC = 0.87) as well as for the CDLSW-HRCT (ICC = 0.94), CDLSW-CBCT (ICC = 0.94) and CDLreference (ICC = 0.87). CONCLUSIONS: All approaches would have led to an electrode choice of rather too short electrodes. Concerning treatment decisions based on CDL measurements, the otosurgical planning software-based method has to be recommended. The best inter-rater reliability was found for CDLA-CBCT, for CDLSW-HRCT, for CDLSW-CBCT, and for CDLreference. KEY POINTS: • Clinically applicable calculations using high-resolution CT and cone beam CT underestimate the cochlear size. • Ten percent of cochlear duct length need to be added to current calculations in order to predict the postoperative CI electrode position. • The clinically approved otosurgical planning software-based method software is the most suitable to estimate the cochlear duct length and shows an excellent inter-rater reliability.


Subject(s)
Cochlear Implantation , Cochlear Implants , Cochlea/diagnostic imaging , Cochlear Duct/surgery , Cone-Beam Computed Tomography , Electrodes, Implanted , Humans , Reproducibility of Results , Temporal Bone/diagnostic imaging , Tomography, X-Ray Computed
12.
Int J Mol Sci ; 23(24)2022 Dec 17.
Article in English | MEDLINE | ID: mdl-36555733

ABSTRACT

Remyelination therapies, which are currently under development, have a great potential to delay, prevent or even reverse disability in multiple sclerosis patients. Several models are available to study the effectiveness of novel compounds in vivo, among which is the cuprizone model. This model is characterized by toxin-induced demyelination, followed by endogenous remyelination after cessation of the intoxication. Due to its high reproducibility and ease of use, this model enjoys high popularity among various research and industrial groups. In this review article, we will summarize recent findings using this model and discuss the potential of some of the identified compounds to promote remyelination in multiple sclerosis patients.


Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Remyelination , Humans , Animals , Mice , Cuprizone/adverse effects , Myelin Sheath , Demyelinating Diseases/chemically induced , Reproducibility of Results , Mice, Inbred C57BL , Disease Models, Animal
13.
Int J Mol Sci ; 23(19)2022 Sep 26.
Article in English | MEDLINE | ID: mdl-36232643

ABSTRACT

Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system's white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.


Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Remyelination , Animals , Cuprizone/toxicity , Demyelinating Diseases/pathology , Disease Models, Animal , Mice , Mice, Inbred C57BL , Multiple Sclerosis/chemically induced , Multiple Sclerosis/pathology , Myelin Sheath/pathology , Rotarod Performance Test
14.
Glia ; 69(4): 925-942, 2021 04.
Article in English | MEDLINE | ID: mdl-33245604

ABSTRACT

The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone-intoxicated mice and post-mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro-inflammatory milieu in the CNS of cuprizone-intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone-intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone-induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.


Subject(s)
Cuprizone , Demyelinating Diseases , Animals , CD8-Positive T-Lymphocytes , Cuprizone/toxicity , Demyelinating Diseases/chemically induced , Disease Models, Animal , Mice , Mice, Inbred C57BL , Oligodendroglia
15.
Immunology ; 164(3): 450-466, 2021 11.
Article in English | MEDLINE | ID: mdl-34293193

ABSTRACT

Ectopic lymphoid follicles (ELFs), resembling germinal centre-like structures, emerge in a variety of infectious and autoimmune and neoplastic diseases. ELFs can be found in the meninges of around 40% of the investigated progressive multiple sclerosis (MS) post-mortem brain tissues and are associated with the severity of cortical degeneration and clinical disease progression. Of predominant importance for progressive neuronal damage during the progressive MS phase appears to be meningeal inflammation, comprising diffuse meningeal infiltrates, B-cell aggregates and compartmentalized ELFs. However, the absence of a uniform definition of ELFs impedes reproducible and comparable neuropathological research in this field. In this review article, we will first highlight historical aspects and milestones around the discovery of ELFs in the meninges of progressive MS patients. In the next step, we discuss how animal models may contribute to an understanding of the mechanisms underlying ELF formation. Finally, we summarize challenges in investigating ELFs and propose potential directions for future research.


Subject(s)
Meninges/pathology , Multiple Sclerosis, Chronic Progressive/immunology , Tertiary Lymphoid Structures/immunology , Animals , B-Lymphocytes/immunology , Disease Models, Animal , Humans , Meninges/immunology , Multiple Sclerosis, Chronic Progressive/pathology , Tertiary Lymphoid Structures/pathology
16.
Neurobiol Dis ; 155: 105371, 2021 07.
Article in English | MEDLINE | ID: mdl-33932559

ABSTRACT

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with episodes of inflammatory demyelination and remyelination. While remyelination has been linked with functional recovery in MS patients, there is evidence of ongoing tissue damage despite complete myelin repair. In this study, we investigated the long-term consequences of an acute demyelinating white matter CNS lesion. For this purpose, acute demyelination was induced by 5-week-cuprizone intoxication in male C57BL/6 J mice, and the tissues were examined after a 7-month recovery period. While myelination and oligodendrocyte densities appeared normal, ongoing axonal degeneration and glia cell activation were found in the remyelinated corpus callosum. Neuropathologies were paralleled by subtle gait abnormalities evaluated using DigiGait™ high speed ventral plane videography. Gene array analyses revealed increased expression levels of various inflammation related genes, among protein kinase c delta (PRKCD). Immunofluorescence stains revealed predominant microglia/macrophages PRKCD expression in both, cuprizone tissues and post-mortem MS lesions. These results support the hypothesis that chronic microglia/macrophages driven tissue injury represents a key aspect of progressive neurodegeneration and functional decline in MS.


Subject(s)
Axons/pathology , Brain/pathology , Inflammation Mediators , Multiple Sclerosis/pathology , Nerve Degeneration/pathology , White Matter/pathology , Animals , Axons/metabolism , Brain/metabolism , Chelating Agents/toxicity , Cuprizone/toxicity , Humans , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , Multiple Sclerosis/psychology , Nerve Degeneration/chemically induced , Nerve Degeneration/genetics , Nerve Degeneration/psychology , White Matter/metabolism
17.
Int J Mol Sci ; 22(15)2021 Jul 27.
Article in English | MEDLINE | ID: mdl-34360808

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.


Subject(s)
Amyotrophic Lateral Sclerosis/immunology , Induced Pluripotent Stem Cells/immunology , Interleukin-17/immunology , Motor Neurons/immunology , RNA-Binding Protein FUS/immunology , Th17 Cells/immunology , Amyotrophic Lateral Sclerosis/pathology , Cell Survival/immunology , Humans , Induced Pluripotent Stem Cells/pathology , Motor Neurons/pathology , Th17 Cells/pathology
18.
Zentralbl Chir ; 146(5): 452-457, 2021 Oct.
Article in German | MEDLINE | ID: mdl-34666356

ABSTRACT

Vascular surgery has developed very dynamically in recent years, especially with the introduction of endovascular techniques. However, this has also changed surgeons' requirements. Classical surgical procedures have been almost completely displaced by endovascular techniques; new hybrid interventions have emerged while complex operations are concentrated in few centres. Therefore, developing expertise in open aortic surgery is increasingly challenging in vascular surgical training programs.Cadaver models provide an opportunity for exposure and repetitive training of individual surgical steps without endangering patients.As part of the training of highly complex vascular surgery operations, we carried out and evaluated the thoracoabdominal aortic replacement with 13 participants in 6 ethanol-preserved corpses.A simulation of surgical procedures on human cadaveric models cannot fully replace real experiences, but allows surgeons in training to practice and achieve dexterity in performing procedures in a safe and reproducible way.


Subject(s)
Endovascular Procedures , Surgeons , Cadaver , Clinical Competence , Education, Medical, Graduate , Humans
19.
Neurobiol Dis ; 134: 104675, 2020 02.
Article in English | MEDLINE | ID: mdl-31731041

ABSTRACT

Accumulating evidence suggests that a degenerative processes within the brain can trigger the formation of new, focal inflammatory lesions in Multiple Sclerosis (MS). Here, we used a novel pre-clinical MS animal model to test whether the amelioration of degenerative brain events reduces the secondary recruitment of peripheral immune cells and, in consequence, inflammatory lesion development. Neural degeneration was induced by a 3 weeks cuprizone intoxication period. To mitigate the cuprizone-induced pathology, animals were treated with Laquinimod (25 mg/kg) during the cuprizone-intoxication period. At the beginning of week 6, encephalitogenic T cell development in peripheral lymphoid organs was induced by the immunization with myelin oligodendrocyte glycoprotein 35-55 peptide (i.e., Cup/EAE). Demyelination, axonal injury and reactive gliosis were determined by immunohistochemistry. Positron emission tomography (PET) imaging was performed to analyze glia activation in vivo. Vehicle-treated cuprizone mice displayed extensive callosal demyelination, glia activation and enhanced TSPO-ligand binding. This cuprizone-induced pathology was profoundly ameliorated in mice treated with Laquinimod. In vehicle-treated Cup/EAE mice, the cuprizone-induced pathology triggered massive peripheral immune cell recruitment into the forebrain, evidenced by multifocal perivascular inflammation, glia activation and neuro-axonal injury. While anti myelin oligodendrocyte glycoprotein 35-55 peptide immune responses were comparable in vehicle- and Laquinimod-treated Cup/EAE mice, the cuprizone-triggered immune cell recruitment was ameliorated by the Laquinimod treatment. This study clearly illustrates that amelioration of a primary brain-intrinsic degenerative process secondary halts peripheral immune cell recruitment and, in consequence, inflammatory lesion development. These findings have important consequences for the interpretation of the results of clinical studies.


Subject(s)
Brain/drug effects , Brain/pathology , Encephalitis/immunology , Encephalitis/pathology , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Quinolones/administration & dosage , Animals , Cuprizone/administration & dosage , Disease Models, Animal , Encephalitis/chemically induced , Female , Gliosis/chemically induced , Gliosis/pathology , Mice, Inbred C57BL
20.
J Neuroinflammation ; 17(1): 325, 2020 Oct 29.
Article in English | MEDLINE | ID: mdl-33121515

ABSTRACT

BACKGROUND: Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. METHODS: Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. RESULTS: Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. CONCLUSIONS: In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.


Subject(s)
Annexin A1/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Encephalitis/drug therapy , Hippocampus/drug effects , Meningitis, Pneumococcal/drug therapy , Neutrophil Infiltration/drug effects , Peptides/therapeutic use , Animals , Annexin A1/pharmacology , Anti-Inflammatory Agents/pharmacology , Mice , Mice, Knockout , Neutrophils/drug effects , Peptides/pharmacology , Receptors, Formyl Peptide/genetics , Treatment Outcome
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