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Ischemic Stroke is a major cause of morbidity and mortality worldwide. Sterile inflammation occurs after both stroke subtypes and contributes to neuronal injury and damage to the blood-brain barrier with release of brain antigens and a potential induction of autoimmune responses that escape central and peripheral tolerance mechanisms. In stroke patients, the detection of T cells and antibodies specific to neuronal antigens suggests a role of humoral adaptive immunity. In experimental models stroke leads to a significant increase of autoreactive T and B cells to CNS antigens. Lesion volume and functional outcome in stroke patients and murine stroke models are connected to antigen-specific responses to brain proteins. In patients with traumatic brain injury (TBI) a range of antibodies against brain proteins can be detected in serum samples. In this review, we will summarize the role of autoimmunity in post-lesional conditions and discuss the role of B and T cells and their potential neuroprotective or detrimental effects.

When a main artery of the brain occludes, a cellular response involving multiple cell types follows. Cells directly affected by the lack of glucose and oxygen in the neuronal core die by necrosis. In the periphery surrounding the ischemic core (the so-called penumbra) neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells react to detrimental factors such as excitotoxicity, oxidative stress, and inflammation in different ways. The fate of the neurons in this area is multifactorial, and communication between all the players is important for survival. This review focuses on the latest research relating to synaptic loss and the release of apoptotic bodies and other extracellular vesicles for cellular communication in stroke. We also point out possible treatment options related to increasing neuronal survival and regeneration in the penumbra.

Ischemic stroke is a major cause of death. Besides the direct damage resulting from oxygen and glucose deprivation, sterile inflammation plays a pivotal role in increasing cellular death. Damaged-associated molecular patterns (DAMPs) are passively released from dying cells and activate the innate immune system. Thus, they take part in the direct and rapid activation of the inflammatory response after stroke onset. In this review the role of the most important DAMPs, high mobility group box 1, heat and cold shock proteins, purines, and peroxiredoxins, are addressed. Moreover, intracellular pathways activated by DAMPs in microglia are illuminated.

In ischemic stroke, the primary neuronal injury caused by the disruption of energy supply is further exacerbated by secondary sterile inflammation. The inflammatory cascade is largely initiated by the purine adenosine triphosphate (ATP) which is extensively released to the interstitial space during brain ischemia and functions as an extracellular danger signaling molecule. By engaging P2 receptors, extracellular ATP activates microglia leading to cytokine and chemokine production and subsequent immune cell recruitment from the periphery which further amplifies post-stroke inflammation. The ectonucleotidases CD39 and CD73 shape and balance the inflammatory environment by stepwise degrading extracellular ATP to adenosine which itself has neuroprotective and anti-inflammatory signaling properties. The neuroprotective effects of adenosine are mainly mediated through A1 receptors and inhibition of glutamatergic excitotoxicity, while the anti-inflammatory capacities of adenosine have been primarily attributed to A2A receptor activation on infiltrating immune cells in the subacute phase after stroke. In this review, we summarize the current state of knowledge on the ATP-adenosine axis in ischemic stroke, discuss contradictory results, and point out potential pitfalls towards translating therapeutic approaches from rodent stroke models to human patients.

Blood neurofilament light chain (NfL) is an easily accessible, highly sensitive and reliable biomarker for neuroaxonal damage. Currently, its role in Parkinson’s disease (PD) remains unclear. Here, we demonstrate that blood NfL can distinguish idiopathic PD from atypical parkinsonian syndromes (APS) with high sensitivity and specificity. In cross-sectional studies, some found significant correlations between blood NfL with motor and cognitive function, whereas others did not. In contrast, prospective studies reported very consistent associations between baseline blood NfL with motor progression and cognitive worsening. Amongst PD subtypes, especially postural instability and gait disorder (PIGD) subtype, symptoms and scores are reliably linked with blood NfL. Different non-motor PD comorbidities have also been associated with high blood NfL levels suggesting that the neuroaxonal damage of the autonomic nervous system as well as serotonergic, cholinergic and noradrenergic neurons is quantifiable. Numerous absolute NfL cutoff levels have been suggested in different cohort studies; however, validation across cohorts remains weak. However, age-adjusted percentiles and intra-individual blood NfL changes might represent more valid and consistent parameters compared with absolute NfL concentrations. In summary, blood NfL has the potential as biomarker in PD patients to be used in clinical practice for prediction of disease severity and especially progression.

Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. The stepwise hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 generates adenosine, a potent immune suppressor. Here we report that human effector CD8 T cells contribute to adenosine production by releasing CD73-containing extracellular vesicles upon activation. These extracellular vesicles have AMPase activity, and the resulting adenosine mediates immune suppression independently of regulatory T cells. In addition, we show that extracellular vesicles isolated from the synovial fluid of patients with juvenile idiopathic arthritis contribute to T cell suppression in a CD73-dependent manner. Our results suggest that the generation of adenosine upon T cell activation is an intrinsic mechanism of human effector T cells that complements regulatory T cell-mediated suppression in the inflamed tissue. Finally, our data underscore the role of immune cell-derived extracellular vesicles in the control of immune responses. Ectonucleotidases associated to regulatory T cells are known modulators in the inflammatory environment. Here the authors describe CD8 T cell-derived extracellular vesicles bearing CD73 and suggest they function as an additional intrinsic modulator of immune responses.

Indoxyl sulfate (IS) is a protein-bound uremic toxin resulting from the metabolism of dietary tryptophan which accumulates in patients with impaired renal function, such as chronic kidney disease (CKD). IS is a well-known nephrovascular toxin but little is known about its effects on central nervous system (CNS) cells. Considering the growing interest in the field of CNS comorbidities in CKD, we studied the effect of IS on CNS cells. IS (15-60 μM) treatment in C6 astrocyte cells increased reactive oxygen species release and decreased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, and heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 expression. Moreover, IS increased Aryl hydrocarbon Receptor (AhR) and Nuclear Factor-kB (NF-kB) activation in these cells. Similiar observations were made in primary mouse astrocytes and mixed glial cells. Inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression, tumor necrosis factor-α and interleukin-6 release and nitrotyrosine formation were increased by IS (15-60 μM) in primary mouse astrocytes and mixed glial cells. IS increased AhR and NF-kB nuclear translocation and reduced Nrf2 translocation and HO-1 expression in primary glial cells. In addition, IS induced cell death in neurons in a dose dependent fashion. Injection of IS (800 mg/kg, i.p.) into mice induced histological changes and increased COX-2 expression and nitrotyrosine formation in thebrain tissue. Taken together, our results show a significant contribution of IS in generating a neurotoxic enviroment and it could also have a potential role in neurodegeneration. IS could be considered also a potential therapeutical target for CKD-associated neurodegenerative complications.

In multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, both resident microglia and infiltrating macrophages contribute to demyelination as well as spontaneous remyelination. Nevertheless, the specific roles of microglia versus macrophages are unknown. We investigated the influence of microglia in EAE using the colony stimulating factor 1 receptor (CSF-1R) inhibitor, PLX5622, to deplete microglial population and Ccr2 RFP/+ fms EGFP/+ mice, to distinguish blood-derived macrophages from microglia. PLX5622 treatment depleted microglia and meningeal macrophages, and provoked a massive infiltration of CCR2 + macrophages into demyelinating lesions and spinal cord parenchyma, albeit it did not alter EAE chronic phase. In contrast, microglia and meningeal macrophages depletion reduced the expression of major histocompatibility complex II and CD80 co-stimulatory molecule in dendritic cells, macrophages and microglia. In addition, it diminished T cell reactivation and proliferation in the spinal cord parenchyma, inducing a significant delay in EAE onset. Altogether, these data point to a specific role of CNS microglia and meningeal macrophages in antigen presentation and T cell reactivation at initial stages of EAE.

Microglia play a crucial role in maintaining homeostasis of the central nervous system and they are actively involved in shaping the brain’s inflammatory response to stress. Among the multitude of involved molecules, purinergic receptors and enzymes are of special importance due to their ability to regulate microglia activation. By investigating the mechanisms underlying microglial responses and dysregulation, researchers can develop more precise interventions to modulate microglial behavior and alleviate neuroinflammatory processes. Studying gene function selectively in microglia, however, remains technically challenging. This review article provides an overview of adeno-associated virus (AAV)-based microglia targeting approaches, discussing potential prospects for refining these approaches to improve both specificity and effectiveness and encouraging future investigations aimed at connecting the potential of AAV-mediated microglial targeting for therapeutic benefit in neurological disorders.

Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen‐ or tissue damage‐induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro‐inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation in vitro and remyelination after lysolecithin‐induced demyelination. Conversely, potentiation of P2X4R signaling by the allosteric modulator ivermectin (IVM) favored a switch in microglia to an anti‐inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE. Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage. Synopsis Innate immune cells contribute to axonal damage and demyelination in multiple sclerosis (MS) but they are also pivotal in promoting repair responses. Modulating microglia/macrophage P2X4R activation determines clinical outcome in the experimental autoimmune encephalomyelitis (EAE) model of MS. Expression of P2x4r and the two transcription factors controlling its expression, Irf8 and Irf5, was increased in EAE. EAE clinical symptoms were exacerbated by P2X4R blockage and ameliorated by P2X4R potentiation with the allosteric modulator ivermectin. P2X4R blockage does not interfere with the immune priming or with blood‐brain‐barrier permeability during the acute phase of EAE. P2X4R activation favors a switch of microglia/macrophage to an anti‐inflammatory phenotype and increases BDNF release, that promotes oligodendrocyte differentiation. P2X4R activation increases myelin phagocytosis and degradation at lysosomes, thus indirectly promoting remyelinating responses. Graphical Abstract Innate immune cells contribute to axonal damage and demyelination in multiple sclerosis (MS) but they are also pivotal in promoting repair responses. Modulating microglia/macrophage P2X4R activation determines clinical outcome in the experimental autoimmune encephalomyelitis (EAE) model of MS.