Immunomodulation induced by central nervous system-related peptides as a therapeutic strategy for neurodegenerative disorders.

Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.

Downregulation of CD151 restricts VCAM-1 mediated leukocyte infiltration to reduce neurobiological injuries after experimental stroke.

BACKGROUND: Translational failures in anti-adhesion molecule therapies after stroke reveal the necessity of developing new strategies that not only interrupt leukocyte recruitment but also consider the inhibition of endothelial cell inflammation, verification of therapeutic time window, and normal function maintenance of circulating leukocytes. Our study focused on the potential therapeutic value of CD151 downregulation in improving current anti-adhesion molecule therapies. METHODS: Lentivirus intracerebroventricular administration was conducted to inhibit the CD151 expression and observe its functional influence on neurological injuries and outcomes. Then, immunohistochemistry and myeloperoxidase activity assessment were performed to explore the effects of CD151 expression on neutrophil and monocyte recruitment after rat cerebral ischemia. Primary rat brain microvascular endothelial cells were subjected to oxygen glucose deprivation and reoxygenation to elucidate the underlying working mechanisms between CD151 and VCAM-1. RESULTS: The CD151 downregulation remarkably reduced neurological injuries and improved neurological outcomes, which were accompanied with reduced neutrophil and monocyte infiltration after the CD151 downregulation. The VCAM-1 expression was remarkably decreased among the adhesion molecules on the endothelial cell responsible for neutrophil and monocyte infiltration. The activation of p38 MAPK and NF-κB pathways was restricted after the CD151 downregulation. p38 MAPK and NF-κB inhibitors decreased the VCAM-1 expression, and p38 acted as an upstream regulator of NF-κB. However, CD151 downregulation did not directly influence the neutrophil and monocyte activation. CONCLUSIONS: Overall, CD151 regulated the expression of adhesion molecules. It also played a critical role in suppressing VCAM-1-mediated neutrophil and monocyte infiltration via the p38/NF-κB pathway. This study possibly provided a new basis for improving current anti-adhesion molecule therapies.

Neurological involvement of COVID-19: from neuroinvasion and neuroimmune crosstalk to long-term consequences.

As the coronavirus disease 2019 (COVID-19) pandemic continues to be a multidimensional threat to humanity, more evidence of neurological involvement associated with it has emerged. Neuroimmune interaction may prove to be important not only in the pathogenesis of neurological manifestations but also to prevent systemic hyperinflammation. In this review, we summarize reports of COVID-19 cases with neurological involvement, followed by discussion of possible routes of entry, immune responses against coronavirus infection in the central nervous system and mechanisms of nerve degeneration due to viral infection and immune responses. Possible mechanisms for neuroprotection and virus-associated neurological consequences are also discussed.

Facilitating the gut brain axis by probiotic bacteria to modulate neuroimmune response on lead exposed zebra fish models

Unravelling the efficacy of gut biome has a major impact on health. An unbalanced microbiome composition is linked to many common illnesses such as gut dysbiosis, mental deformities and immunological imbalance. An optimistic influence on the gut biome can be made by consumingprobiotics. This would stimulate neuroprotection and immunomodulation intended by heavy metals pollution. Lead is a major source of neurotoxin that can induce neural deformities. Lactobacillusspecies isolated from curd were characterized to confirm its specificity. Zebra fish was reared at standard conditions and preclinical assessment on the intensity of induced neurotoxin lead was performed. The embryo toxic assay, immunomodulation effects and animal behavioural models endorsed the consequence of neurotoxicity. Different concentrations of bacterial isolate with standard antidepressant was considered for analysing the vigour of toxicity and its influence on cognitive behaviour by novel tank diving method. The restrain in the animal behaviour was also conferred by all the test samples with a decreased bottom dwelling time which was authenticated with haematology and histopathological studies. The alterations in morphology of the lymphocytes were balanced by the treated test samples. This study paves a twofold potential of probiotic as neuroprotectant and immune modulator against heavy metal toxicity.

Filling the gaps on stroke research: Focus on inflammation and immunity.

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.

Neuroprotective Methodologies in the Treatment of Multiple Sclerosis Current Status of Clinical and Pre-clinical Findings.

Multiple sclerosis is an idiopathic and autoimmune associated motor neuron disorder that affects myelinated neurons in specific brain regions of young people, especially females. MS is characterized by oligodendrocytes destruction further responsible for demyelination, neuroinflammation, mitochondrial abnormalities, oxidative stress and neurotransmitter deficits associated with motor and cognitive dysfunctions, vertigo and muscle weakness. The limited intervention of pharmacologically active compounds like interferon-ß, mitoxantrone, fingolimod and monoclonal antibodies used clinically are majorly associated with adverse drug reactions. Pre-clinically, gliotoxin ethidium bromide mimics the behavioral and neurochemical alterations in multiple sclerosis- like in experimental animals associated with the down-regulation of adenyl cyclase/cAMP/CREB, which is further responsible for a variety of neuropathogenic factors. Despite the considerable investigation of neuroprotection in curing multiple sclerosis, some complications still remain. The available medications only provide symptomatic relief but do not stop the disease progression. In this way, the development of unused beneficial methods tends to be ignored. The limitations of the current steady treatment may be because of their activity at one of the many neurotransmitters included or their failure to up direct signaling flag bearers detailed to have a vital part in neuronal sensitivity, biosynthesis of neurotransmitters and its discharge, development, and separation of the neuron, synaptic versatility and cognitive working. Therefore, the current review strictly focused on the exploration of various clinical and pre-clinical features available for multiple sclerosis to understand the pathogenic mechanisms and to introduce pharmacological interventions associated with the upregulation of intracellular adenyl cyclase/cAMP/CREB activation to ameliorate multiple sclerosis-like features.

Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs.

A wide array of molecular pathways has been investigated during the past decade in order to understand the mechanisms by which the practice of physical exercise promotes neuroprotection and reduces the risk of developing communicable and non-communicable chronic diseases. While a single session of physical exercise may represent a challenge for cell homeostasis, repeated physical exercise sessions will improve immunosurveillance and immunocompetence. Additionally, immune cells from the central nervous system will acquire an anti-inflammatory phenotype, protecting central functions from age-induced cognitive decline. This review highlights the exercise-induced anti-inflammatory effect on the prevention or treatment of common chronic clinical and experimental settings. It also suggests the use of pterins in biological fluids as sensitive biomarkers to follow the anti-inflammatory effect of physical exercise.

Early life neuroimmune challenge protects the brain after sepsis in adult rats.

Evidences has suggested that in the early life the innate immune system presents plasticity and the time and dose-adequate stimuli in this phase may program long-lasting immunological responses that persist until adulthood. We aimed to evaluate whether LPS challenge in early childhood period may modulate brain alterations after sepsis in adult life. Experiments were performed to evaluate the LPS challenge in early childhood or adult period on acute and long-term brain alterations after model of sepsis by cecal ligation and perforation (CLP) in adult life. Wistar rats were divided in saline+sham, LPS+sham, saline+CLP and LPS+CLP groups to determine cytokine levels and nitrite/nitrate concentration in cerebrospinal fluid (CSF); oxidative damage, activity of antioxidant enzymes (superoxide dismutase-SOD and catalase-CAT); blood brain barrier (BBB) permeability; myeloperoxidase (MPO) and epigenetic enzymes activities in the hippocampus and prefrontal cortex (at 24 h after CLP) and cognitive function, survival and brain-derived neurotrophic factor (BDNF) level (at ten days after CLP). LPS-preconditioning in early life could lead to decreased levels of TNF-α and IL-6 and oxidative damage parameters in the brain after CLP in adult rats. In addition, LPS-preconditioning in early life increase CAT activity, attenuates the BBB permeability and epigenetic enzymes alterations and in long term, improves the memory, BDNF levels and survival. In conclusion, rats submitted to CLP in adulthood displayed acute neuroinflammation, neurochemical and epigenetic alteration improvement accompanied in long term by an increase in survival, neurotrophin level and memory performance when preconditioned with LPS in the early life.

Regulatory T cell is critical for interleukin-33-mediated neuroprotection against stroke.

Interleukin-33 (IL-33) is known to activate the regulatory T lymphocytes (Tregs), which are negatively correlated with brain damage after ischemic stroke. In this study, we aimed to investigate the role of Tregs in IL-33-mediated neuroprotection and elucidate the underlying mechanisms. In vivo, male C57BL/6 N mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO), followed by daily administration of vehicle or IL-33 immediately after injury. Tregs were depleted by intraperitoneal administration of anti-CD25 antibody (anti-CD25Ab). Behavioral changes, brain edema, neuronal injury, Treg percentages, and cytokine expression levels were investigated in each group. In vitro experiments, primary mouse neuronal cells were subjected to oxygen-glucose deprivation (OGD) for 3 h. Vehicle- or drug-conditioned Tregs were applied to the neurons at the time of induction of hypoxia. Neuronal apoptosis and cytokine expression were measured in each group. The results indicate that intraperitoneal administration of anti-CD25Ab reduced CD4 + CD25 + Foxp3+ Tregs, increased infarct volume, enhanced stroke-induced cell death, and decreased sensorimotor functions. Notably, IL-33 increased CD4 + CD25 + Foxp3+ Tregs in the spleen and brain. However, blockading ST2 attenuated these effects of IL-33. The supernatant of the IL-33-treated Treg culture reduced neuronal apoptosis and elevated the production of the Treg cytokines IL-10, IL-35, and transforming growth factor-ß (TGF-ß). Anti-CD25Ab abrogated the neuroprotective effect of IL-33. Mechanistically, the neuroprotective effects of IL-33 were associated with reduction in apoptosis-related proteins and production of Tregs related cytokines. Overall, these findings showed that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation via a mechanism involving anti-apoptosis proteins and cytokines, representing a promising immune modulatory target for the treatment of stroke.

Reward and immune responses in adolescent females following experimental traumatic brain injury.

The pathology of traumatic brain injury (TBI) adversely affects many brain regions, often resulting in the development of comorbid psychiatric disorders including substance use disorders (SUD). Although traditionally thought to be an epidemic that predominantly affects males, recent clinical studies report females have higher rates of concussions and longer recovery times than males. Yet, how neurotrauma, particularly deep within the brain, between the sexes is differentially manifested remains largely unknown. The risk of TBI peaks during adolescence when neuronal networks that regulate reward behaviors are not fully developed. Previously, using the conditioned place preference (CPP) assay, we found that adolescent TBI increased susceptibility to the rewarding effects of cocaine in male mice. Further, we observed augmented inflammatory profiles, increased microglial phagocytosis of neuronal proteins, and decreased neuronal spine density in the NAc. Notably, the extent of sex differences in SUD susceptibility following TBI has not be investigated. Thus, here we ask the central question of whether the adolescent TBI-induced neuroinflammatory profile at reward centers is divergent in a sex-dependent manner. Using the CPP assay, we found that female mice with high levels of female sex hormones at the time of adolescent TBI demonstrated neuroprotection against increased sensitivity to the rewarding effects of cocaine. These studies also provide evidence of significantly reduced microglial activation and phagocytosis of neuronal proteins within the NAc of females. Overall, our results offer crucial insight into how adolescent TBI impacts the reward pathway in a sex depending manner that could explain a vulnerability to addiction-like behavior.

N2 neutrophils may participate in spontaneous recovery after transient cerebral ischemia by inhibiting ischemic neuron injury in rats.

Neutrophils have been traditionally considered as the major mediators of harmful inflammatory responses in ischemic stroke, whereas accumulating evidence indicates that neutrophils can be polarized into an N2 phenotype. Similar to M2 microglia, N2 neutrophils contribute to resolution of inflammation and may participate in neuroprotection. However, it remains unclear whether N2 neutrophils protect ischemic neurons and whether they are associated with long-term outcomes after transient cerebral ischemia in rats. The present study proved that N2 neutrophils protected against oxygen glucosedeprivation/re-oxygenation (OGD/R)-induced primary cortical neuron injury via brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signaling. In addition, in vivo studies revealed that transient middle cerebral artery occlusion (tMCAO)-induced injury exhibited spontaneous recovery over time in rats. Moreover, neutrophils could infiltrate the ipsilateral brain parenchyma from the periphery after transient cerebral ischemia. Pearson's correlation analysis indicated that the proportion of N2 neutrophils in ipsilateral brain parenchyma was negatively correlated with the number of degenerating neurons, modified Neurological Severity Score (mNSS), brain water content and infarct volume, and positively correlated with the number of surviving neurons and grip strength. In summary, the present study shows that N2 neutrophils likely participate in spontaneous recovery after transient cerebral ischemia by inhibiting ischemic neuron damage in rats, which indicates that N2 neutrophils may represent promising therapeutic target for promoting recovery after ischemic stroke.

The benefits of neuroinflammation for the repair of the injured central nervous system.

Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia. The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements, which manifest as a heterogeneous set of neurological symptoms. However, it is now readily acknowledged, due to instructive studies from the peripheral nervous system and a large body of CNS literature, that aspects of the neuroinflammatory response can be beneficial for CNS outcomes. The recognized benefits of inflammation to the CNS include the preservation of CNS constituents (neuroprotection), the proliferation and maturation of various neural precursor populations, axonal regeneration, and the reformation of myelin on denuded axons. Herein, we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis, traumatic spinal cord injury, stroke, and Alzheimer's disease. We focus on CNS regenerative responses, such as neurogenesis, axonal regeneration, and remyelination, and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS. Finally, we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.

Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery.

In addition to maintaining immune tolerance, FOXP3+ regulatory T (Treg) cells perform specialized functions in tissue homeostasis and remodelling1,2. However, the characteristics and functions of brain Treg cells are not well understood because there is a low number of Treg cells in the brain under normal conditions. Here we show that there is massive accumulation of Treg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain Treg cells are similar to Treg cells in other tissues such as visceral adipose tissue and muscle3-5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT7. The amplification of brain Treg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain Treg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that Treg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.

The changes of systemic immune responses during the neuroprotection induced by remote ischemic postconditioning against focal cerebral ischemia in mice.

Objective: Remote limb ischemic postconditioning (RIPostC) protects the brain from damage induced by transient focal ischemia/reperfusion. However, the underlying mechanism remains unclear. Methods: RIPostC induced by 10 min of occlusion and another 10 min releasing of blood flow for three cycles in the hind limbs was performed immediately after the reperfusion in a focal ischemia mice model. Neurological scores, immune cell population in the blood, spleen and lymph node, and inflammatory factors in the blood and brain were analyzed 2 days after the reperfusion. Results: Our results demonstrate that RIPostC reduced cerebral injuries and improved neurological functions 2 days after reperfusion. RIPostC significantly inhibited the reduction in the percentage of CD4 T cells in the spleen and lymph node, CD8 T cells in the blood and lymph node, and natural killer T (NKT) cells in the spleen by flow cytometry analysis. RIPostC attenuated the increase of B cells and NK cells in the spleen and noninflammatory monocytes in the blood. The cytokine assay showed that RIPostC decreased the elevation of IL-10, IL-6, and TNF-α in the blood after ischemia. The quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) results indicated that the mRNA level of IL-4 in the brain increased in the middle cerebral artery occlusion mice after RIPostC treatment. Conclusions: The present study indicates that there were significant changes of inflammatory responses during the neuroprotection induced by RIPostC in stroke mice.

Activation of GPR55 induces neuroprotection of hippocampal neurogenesis and immune responses of neural stem cells following chronic, systemic inflammation.

New neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV-1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia. Recent studies have shown a neuroprotective role on NSCs of cannabinoid receptor activation. Yet, little is known about the effects of GPR55, a candidate cannabinoid receptor, activation on reductions of neurogenesis in response to inflammatory insult. In the present study, we examined NSCs exposed to IL-1ß in vitro to assess inflammation-caused effects on NSC differentiation and the ability of GPR55 agonists to attenuate NSC injury. NSC differentiation and neurogenesis was determined via immunofluorescence and flow cytometric analysis of NSC markers (Nestin, Sox2, DCX, S100ß, ßIII Tubulin, GFAP). GPR55 agonist treatment protected against IL-1ß induced reductions in neurogenesis rates. Moreover, inflammatory cytokine receptor mRNA expression was down regulated by GPR55 activation in a neuroprotective manner. To determine inflammatory responses in vivo, we treated C57BL/6 and GPR55-/- mice with LPS (0.2 mg/kg/day) continuously for 14 days via osmotic mini-pump. Reductions in NSC survival (as determined by BrdU incorporation), immature neurons, and neuroblast formation due to LPS were attenuated by concurrent direct intrahippocampal administration of the GPR55 agonist, O-1602 (4 µg/kg/day). Molecular analysis of the hippocampal region showed a suppressed ability to regulate immune responses by GPR55-/- animals manifesting in a prolonged inflammatory response (IL-1ß, IL-6, TNFα) after chronic, systemic inflammation as compared to C57BL/6 animals. Taken together, these results suggest a neuroprotective role of GPR55 activation on NSCs in vitro and in vivo and that GPR55 provides a novel therapeutic target against negative regulation of hippocampal neurogenesis by inflammatory insult.

Various strategies to improve efficacy of stem cell transplantation in multiple sclerosis: Focus on mesenchymal stem cells and neuroprotection.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which predominantly affect young adults and undergo heavy socioeconomic burdens. Conventional therapeutic modalities for MS mostly downregulate aggressive immune responses and are almost insufficient for management of progressive course of the disease. Mesenchymal stem cells (MSCs), due to both immunomodulatory and neuroprotective properties have been known as practical cells for treatment of neurodegenerative diseases like MS. However, clinical translation of MSCs is associated with some limitations such as short-life engraftment duration, little in vivo trans-differentiation and restricted accessibility into damaged sites. Therefore, laboratory manipulation of MSCs can improve efficacy of MSCs transplantation in MS patients. In this review, we discuss several novel approaches, which can potentially enhance MSCs capabilities for treating MS.

Endogenous Protection from Ischemic Brain Injury by Preconditioned Monocytes.

Exposure to low-dose lipopolysaccharide (LPS) before cerebral ischemia is neuroprotective in stroke models, a phenomenon termed preconditioning (PC). Although it is well established that LPS-PC induces central and peripheral immune responses, the cellular mechanisms modulating ischemic injury remain unclear. Here, we investigated the role of immune cells in the brain protection afforded by PC and tested whether monocytes may be reprogrammed by ex vivo LPS exposure, thus modulating inflammatory injury after cerebral ischemia in male mice. We found that systemic injection of low-dose LPS induces a Ly6Chi monocyte response that protects the brain after transient middle cerebral artery occlusion (MCAO) in mice. Remarkably, adoptive transfer of monocytes isolated from preconditioned mice into naive mice 7 h after transient MCAO reduced brain injury. Gene expression and functional studies showed that IL-10, inducible nitric oxide synthase, and CCR2 in monocytes are essential for neuroprotection. This protective activity was elicited even if mouse or human monocytes were exposed ex vivo to LPS and then injected into male mice after stroke. Cell-tracking studies showed that protective monocytes are mobilized from the spleen and reach the brain and meninges, where they suppress postischemic inflammation and neutrophil influx into the brain parenchyma. Our findings unveil a previously unrecognized subpopulation of splenic monocytes capable of protecting the brain with an extended therapeutic window and provide the rationale for cell therapies based on the delivery of autologous or allogeneic protective monocytes in patients after ischemic stroke.SIGNIFICANCE STATEMENT Inflammation is a key component of the pathophysiology of the brain in stroke, a leading cause of death and disability with limited therapeutic options. Here, we investigate endogenous mechanisms of protection against cerebral ischemia. Using lipopolysaccharide (LPS) preconditioning (PC) as an approach to induce ischemic tolerance in mice, we found generation of neuroprotective monocytes within the spleen, from which they traffic to the brain and meninges, suppressing postischemic inflammation. Importantly, systemic LPS-PC can be mimicked by adoptive transfer of in vitro-preconditioned mouse or human monocytes at translational relevant time points after stroke. This model of neuroprotection may facilitate clinical efforts to increase the efficacy of BM mononuclear cell treatments in acute neurological diseases such as cerebral ischemia.

Promises and limitations of immune cell-based therapies in neurological disorders.

The healthy immune system has natural checkpoints that temper pernicious inflammation. Cells mediating these checkpoints include regulatory T cells, regulatory B cells, regulatory dendritic cells, microglia, macrophages and monocytes. Here, we highlight discoveries on the beneficial functions of regulatory immune cells and their mechanisms of action and evaluate their potential use as novel cell-based therapies for brain disorders. Regulatory immune cell therapies have the potential not only to mitigate the exacerbation of brain injury by inflammation but also to promote an active post-injury brain repair programme. By harnessing the reparative properties of these cells, we can reduce over-reliance on medications that mask clinical symptoms but fail to impede or reverse the progression of brain disorders. Although these discoveries encourage further testing and genetic engineering of regulatory immune cells for the clinical management of neurological disorders, a number of challenges must be surmounted to improve their safety and efficacy in humans.

miR-221 alleviates the inflammatory response and cell apoptosis of neuronal cell through targeting TNFAIP2 in spinal cord ischemia-reperfusion.

This study aimed to examine the role of miR-221 in inflammatory response and apoptosis of neuronal cells after spinal cord ischemia/reperfusion (I/R) injury. Blood samples were obtained from 20 I/R patients and that of 20 healthy individuals were used as a control. AGE1.HN and SY-SH-5Y neuronal cell lines subjected to oxygen-glucose deprivation (OGD) stress were used in cell experiments. Real-time PCR and western blot were used to evaluate the expression of miR-221, tumor necrosis factor-α, and TNFAIP2. TUNEL assay analyzed cell apoptosis. I/R patients had lower serum levels of miR-221 than healthy controls. In OGD-AGE1.HN and SY-SH-5Y cells, miR-221 was significantly downregulated and TNFAIP2 mRNA and protein were upregulated; meanwhile, both proinflammatory cytokine tumor necrosis factor-α and anti-inflammation cytokine interleukin-6 were elevated and the percentage of apoptotic cells was increased. This inflammatory response and cell apoptosis induced by OGD stress were attenuated by miR-221 overexpression and enhanced by miR-221 knockdown. TNFAIP2 is a target gene for miR-221 and could be regulated negatively by the miR-221 mimic or the miR-221 inhibitor with or without OGD stress. Accordingly, TNFAIP2 overexpression reversed the inflammatory response and cell apoptosis induced by miR-221 under OGD stress. Downregulation of miR-221 occurs in spinal cord I/R injury and in cell lines subjected to oxygen-glucose deprivation. miR-221 regulates the inflammatory response and apoptosis of neuronal cells through its impact on TNFAIP2.

Inhibition of HMGB1 mediates neuroprotection of traumatic brain injury by modulating the microglia/macrophage polarization.

Microglia/Macrophages have a double-edged role in secondary brain damage after traumatic brain injury (TBI) depending on polarization toward proinflammatory M1 or anti-inflammatory M2 phenotypes. Recently, high-mobility group box 1 (HMGB1) was found to influence the polarization of macrophages. In this study, glycyrrhizin (GL), an inhibitor of HMGB1, was used to investigate whether the inhibition of HMGB1 could modulate microglia/macrophage polarization after TBI. The results showed that treatment with GL improved the neurological function recovery, reduced the lesion volume, and inhibited the release and expression of HMGB1 after TBI. In addition, the administration of GL suppressed M1 phenotype activation and promoted M2 phenotype activation of microglia/macrophages. In conclusion, the results suggested that GL attenuated TBI by inhibiting M1 phenotype while inducing M2 phenotype activation of microglia/macrophages, at least partly through inhibiting HMGB1. Also, targeting HMGB1 to modulate the microglia/macrophage polarization should be one potential therapeutic approach for TBI.