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Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question whether ChP volumes could act as an interspecies marker of neuroinflammation that closely interrelates with functional impairment. Therefore, we explore ChP characteristics in neuroinflammation in patients with multiple sclerosis and in two experimental mouse models, cuprizone diet-related demyelination and experimental autoimmune encephalomyelitis. We demonstrate that ChP enlargement—reconstructed from MRI—is highly associated with acute disease activity, both in the studied mouse models and in humans. A close dependency of ChP integrity and molecular signatures of neuroinflammation is shown in the performed transcriptomic analyses. Moreover, pharmacological modulation of the blood–CSF barrier with natalizumab prevents an increase of the ChP volume. ChP enlargement is strongly linked to emerging functional impairment as depicted in the mouse models and in multiple sclerosis patients. Our findings identify ChP characteristics as robust and translatable hallmarks of acute and ongoing neuroinflammatory activity in mice and humans that could serve as a promising interspecies marker for translational and reverse-translational approaches.

Sodium chloride promotes vascular fibrosis, arterial hypertension, pro-inflammatory immune cell polarization and endothelial dysfunction, all of which might influence outcomes following stroke. But despite enormous translational relevance, the functional importance of sodium chloride in the pathophysiology of acute ischemic stroke is still unclear. In the current study, we show that high-salt diet leads to significantly worse functional outcomes, increased infarct volumes, and a loss of astrocytes and cortical neurons in acute ischemic stroke. While analyzing the underlying pathologic processes, we identified the migrasome as a novel, sodium chloride-driven pathomechanism in acute ischemic stroke. The migrasome was previously described in vitro as a migrating organelle, which incorporates and dispatches cytosol of surrounding cells and plays a role in intercellular signaling, whereas a pathophysiological meaning has not been elaborated. We here confirm previously reported characteristics of the migrasome in vivo. Immunohistochemistry, electron microscopy and proteomic analyses further demonstrate that the migrasome incorporates and dispatches cytosol of surrounding neurons following stroke. The clinical relevance of these findings is emphasized by neuropathological examinations, which detected migrasome formation in infarcted brain parenchyma of human stroke patients. In summary, we demonstrate that high-salt diet aggravates stroke outcomes, and we characterize the migrasome as a novel mechanism in acute stroke pathophysiology.

Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.

Background Cladribine is a synthetic purine analogue that interferes with DNA synthesis and repair next to disrupting cellular proliferation in actively dividing lymphocytes. The compound is approved for the treatment of multiple sclerosis (MS). Cladribine can cross the blood–brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. Here, we explored compartment-specific immunosuppressive as well as potential direct neuroprotective effects of oral cladribine treatment in experimental autoimmune encephalomyelitis (EAE) mice. Methods In the current study, we compare immune cell frequencies and phenotypes in the periphery and CNS of EAE mice with distinct grey and white matter lesions (combined active and focal EAE) either orally treated with cladribine or vehicle, using flow cytometry. To evaluate potential direct neuroprotective effects, we assessed the integrity of the primary auditory cortex neuronal network by studying neuronal activity and spontaneous synaptic activity with electrophysiological techniques ex vivo. Results Oral cladribine treatment significantly attenuated clinical deficits in EAE mice. Ex vivo flow cytometry showed that cladribine administration led to peripheral immune cell depletion in a compartment-specific manner and reduced immune cell infiltration into the CNS. Histological evaluations revealed no significant differences for inflammatory lesion load following cladribine treatment compared to vehicle control. Single cell electrophysiology in acute brain slices was performed and showed an impact of cladribine treatment on intrinsic cellular firing patterns and spontaneous synaptic transmission in neurons of the primary auditory cortex. Here, cladribine administration in vivo partially restored cortical neuronal network function, reducing action potential firing. Both, the effect on immune cells and neuronal activity were transient. Conclusions Our results indicate that cladribine exerts a neuroprotective effect after crossing the blood–brain barrier independently of its peripheral immunosuppressant action.

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, the role of each central nervous system (CNS)-resident cell type during inflammation, neurodegeneration, and remission has been frequently addressed. Although protocols for the isolation of different individual CNS-resident cell types exist, none can harvest all of them within a single experiment. In addition, isolation of individual cells is more demanding in adult mice and even more so from the inflamed CNS. Here, we present a protocol for the simultaneous purification of viable single-cell suspensions of all principal CNS-resident cell types (microglia, oligodendrocytes, astrocytes, and neurons) from adult mice—applicable in healthy mice as well as in EAE. After dissociation of the brain and spinal cord from adult mice, microglia, oligodendrocytes, astrocytes and, neurons were isolated via magnetic-activated cell sorting (MACS). Validations comprised flow cytometry, immunocytochemistry, as well as functional analyses (immunoassay and Sholl analysis). The purity of each cell isolation averaged 90%. All cells displayed cell-type-specific morphologies and expressed specific surface markers. In conclusion, this new protocol for the simultaneous isolation of all major CNS-resident cell types from one CNS offers a sophisticated and comprehensive way to investigate complex cellular networks ex vivo and simultaneously reduce mice numbers to be sacrificed.

In its first 20 years of operation, the International Criminal Court (ICC) struggled with its limited jurisdiction, the complexity of international criminal proceedings, a lack of support from member states and political pressure. Nevertheless, the Rome Statute still is a milestone of modern international criminal law with high symbolic value, as it contains a clear condemnation of international crimes by the international community. In addition, the ICC encourages the national prosecution of international crimes and thus is the center of the multi-level international criminal justice system.

Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white and grey matter regions. While inflammation is present at all stages of MS, it is more pronounced in the relapsing forms of the disease, whereas progressive MS (PMS) shows significant neuroaxonal damage and grey and white matter atrophy. Hence, disease-modifying treatments beneficial in patients with relapsing MS have limited success in PMS. BAF312 (siponimod) is a novel sphingosine-1-phosphate receptor modulator shown to delay progression in PMS. Besides reducing inflammation by sequestering lymphocytes in lymphoid tissues, BAF312 crosses the blood-brain barrier and binds its receptors on neurons, astrocytes and oligodendrocytes. To evaluate potential direct neuroprotective effects, BAF312 was systemically or locally administered in the CNS of experimental autoimmune encephalomyelitis mice with distinct grey- and white-matter lesions (focal experimental autoimmune encephalomyelitis using an osmotic mini-pump). Ex-vivo flow cytometry revealed that systemic but not local BAF312 administration lowered immune cell infiltration in animals with both grey and white matter lesions. Ex-vivo voltage-sensitive dye imaging of acute brain slices revealed an altered spatio-temporal pattern of activation in the lesioned cortex compared to controls in response to electrical stimulation of incoming white-matter fiber tracts. Here, BAF312 administration showed partial restore of cortical neuronal circuit function. The data suggest that BAF312 exerts a neuroprotective effect after crossing the blood-brain barrier independently of peripheral effects on immune cells. Experiments were carried out in accordance with German and EU animal protection law and approved by local authorities (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen; 87-51.04.2010.A331) on December 28, 2010.

German Chancellor Angela Merkel favours, as a matter of principle, a hard and clean Brexit. This does not mean, however, that it is not in Germany’s interest to maintain a close relationship with the UK in the field of criminal justice cooperation. Thus, from a German perspective it would certainly be desirable if the UK continues to participate in European institutions like Europol and Eurojust. As to mutual assistance it seems, in contrast, questionable how the European Criminal Justice System based on mutual recognition and trust can reach out to a State who is in the course of leaving the Union. In this respect, the extradition of own nationals, prohibited by the German Basic Law in principle, is a crucial issue.

Der Internationale Strafgerichtshof (IStGH) in Den Haag verfolgt seit 2002 das Verbrechen der Aggression, Kriegsverbrechen, Völkermord sowie Verbrechen gegen die Menschlichkeit. Die völkerstrafrechtlichen Anforderungen für eine Klassifizierung als Verbrechen der Aggression sind zwar sehr hoch, dürften im Falle von Russlands Angriff auf die Ukraine aber erfüllt sein. Der IStGH kann in diesem Fall seine Gerichtsbarkeit jedoch nur dann ausüben, wenn sich die Tat aus der Angriffshandlung eines Vertragsstaates ergibt. Russland hat jedoch das Statut nicht unterzeichnet. Die übrigen drei völkerrechtlichen Kernverbrechen können hingegen sowohl vor dem IStGH als auch vor deutschen Gerichten angeklagt werden. Die Liste möglicher Kriegsverbrechen und der Verbrechen gegen die Menschlichkeit, die Russlands Armee in der Ukraine begangen haben, ist lang. Der Nachweis ist jedoch nicht einfach. Schwierig ist dies im Falle des Völkermords. Hier verlangt die internationale Rechtsprechung grundsätzlich, dass der Täter die physisch-biologische Zerstörung der Gruppe angestrebt hat. Since 2002, the International Criminal Court (ICC) in The Hague has been prosecuting crimes of aggression, war crimes, genocide, and crimes against humanity. The legal requirements to constitute a crime of aggression may be very high under international criminal law, but they are likely to be met in the case of Russia’s attack on Ukraine. However, in this case, the ICC can only exercise its jurisdiction if the act results from the aggressive act of a signatory state. But Russia has not signed the statute. The other three core crimes defined by international law, on the other hand, can be prosecuted before both the ICC and German courts. The list of possible war crimes and crimes against humanity committed by Russia’s army in Ukraine is long. However, proving them is not easy. This is difficult in the case of genocide. Here, international jurisprudence basically requires proof that the perpetrator was striving for the physical, biological destruction of the group.

Der Internationale Strafgerichtshof (IStGH) in Den Haag verfolgt seit 2002 das Verbrechen der Aggression, Kriegsverbrechen, Völkermord sowie Verbrechen gegen die Menschlichkeit. Die völkerstrafrechtlichen Anforderungen für eine Klassifizierung als Verbrechen der Aggression sind zwar sehr hoch, dürften im Falle von Russlands Angriff auf die Ukraine aber erfüllt sein. Der IStGH kann in diesem Fall seine Gerichtsbarkeit jedoch nur dann ausüben, wenn sich die Tat aus der Angriffshandlung eines Vertragsstaates ergibt. Russland hat jedoch das Statut nicht unterzeichnet. Die übrigen drei völkerrechtlichen Kernverbrechen können hingegen sowohl vor dem IStGH als auch vor deutschen Gerichten angeklagt werden. Die Liste möglicher Kriegsverbrechen und der Verbrechen gegen die Menschlichkeit, die Russlands Armee in der Ukraine begangen haben, ist lang. Der Nachweis ist jedoch nicht einfach. Schwierig ist dies im Falle des Völkermords. Hier verlangt die internationale Rechtsprechung grundsätzlich, dass der Täter die physisch-biologische Zerstörung der Gruppe angestrebt hat. Since 2002, the International Criminal Court (ICC) in The Hague has been prosecuting crimes of aggression, war crimes, genocide, and crimes against humanity. The legal requirements to constitute a crime of aggression may be very high under international criminal law, but they are likely to be met in the case of Russia’s attack on Ukraine. However, in this case, the ICC can only exercise its jurisdiction if the act results from the aggressive act of a signatory state. But Russia has not signed the statute. The other three core crimes defined by international law, on the other hand, can be prosecuted before both the ICC and German courts. The list of possible war crimes and crimes against humanity committed by Russia’s army in Ukraine is long. However, proving them is not easy. This is difficult in the case of genocide. Here, international jurisprudence basically requires proof that the perpetrator was striving for the physical, biological destruction of the group.