Neuroinflammation In Central Nervous System Research Articles

Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases.

As a protein of the orphan nuclear receptor Nr4a family, Nr4a3 has no identified natural ligands. However, its biological activity can be mediated by inducing conformational changes through interactions with specific certain small molecules and receptors. Nr4a3 is activated as an early stress factor under various pathological conditions and plays a regulatory role in various tissues and cells, participating in processes such as cell differentiation, apoptosis, metabolism, and homeostasis. At present, research on the role of Nr4a3 in the pathophysiology of inflammation is considerably limited, especially with respect to its role in the central nervous system (CNS). In this review, we discuss the role of Nr4a3 in multiple sclerosis, Alzheimer's disease, retinopathy, Parkinson's disease, and other CNS diseases. This review shows that Nr4a3 has considerable potential as a therapeutic target in the treatment of CNS diseases. We provide a theoretical basis for the targeted therapy of CNS diseases and neuroinflammation, among other conditions.

Limitations of PLX3397 as a microglial investigational tool: peripheral and off-target effects dictate the response to inflammation.

Microglia, the resident macrophages of the central nervous system (CNS), play a critical role in CNS homeostasis and neuroinflammation. Pexidartinib (PLX3397), a colony-stimulating factor 1 (CSF1) receptor inhibitor, is widely used to depletemicroglia, offering flexible options for both long-term depletion andhighly versatile depletion-repopulation cycles. However, the potential impact of PLX3397 on peripheral (immune) cells remains controversial. Until now, the microglia-specificity of this type of compounds has not been thoroughly evaluated, particularly in the context of peripherally derived neuroinflammation. Our study addresses this gap by examining the effects of PLX3397 on immune cells in the brain, liver, circulation and bone marrow, both in homeostasis and systemic inflammation models. Intriguingly, we demonstrate that PLX3397 treatment not only influences the levels of tissue-resident macrophages, but also affects circulating and bone marrow immune cells beyond the mononuclear phagocyte system (MPS). These alterations in peripheral immune cells disrupt the response to systemic inflammation, consequently impacting the phenotype irrespective of microglial depletion. Furthermore, we observed that a lower dose of PLX3397, which does not deplete microglia, demonstrates similar (non-)MPS effects, both in the periphery and the brain, but fails to fully replicate the peripheral alterations seen in the higher doses, questioning lower doses as a 'peripheral control' strategy. Overall, our data highlight the need for caution when interpreting studies employing this compound, as it may not be suitable for specific investigation of microglial function in the presence of systemic inflammation.

Adult-Onset CNS Sulfatide Deficiency Causes Sex-Dependent Metabolic Disruption in Aging.

The interconnection between obesity and central nervous system (CNS) neurological dysfunction has been widely appreciated. Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose-intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found that increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypothalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food intake.

Central nervous system demyelinating diseases: glial cells at the hub of pathology.

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice

BackgroundDepression and dysosmia have been regarded as primary neurological symptoms in COVID-19 patients, the mechanism of which remains unclear. Current studies have demonstrated that the SARS-CoV-2 envelope (E) protein is a pro-inflammatory factor sensed by Toll-like receptor 2 (TLR2), suggesting the pathological feature of E protein is independent of viral infection. In this study, we aim to ascertain the role of E protein in depression, dysosmia and associated neuroinflammation in the central nervous system (CNS).MethodsDepression-like behaviors and olfactory function were observed in both female and male mice receiving intracisternal injection of E protein. Immunohistochemistry was applied in conjunction with RT-PCR to evaluate glial activation, blood–brain barrier status and mediators synthesis in the cortex, hippocampus and olfactory bulb. TLR2 was pharmacologically blocked to determine its role in E protein-related depression-like behaviors and dysosmia in mice.ResultsIntracisternal injection of E protein evoked depression-like behaviors and dysosmia in both female and male mice. Immunohistochemistry suggested that the E protein upregulated IBA1 and GFAP in the cortex, hippocampus and olfactory bulb, while ZO-1 was downregulated. Moreover, IL-1β, TNF-α, IL-6, CCL2, MMP2 and CSF1 were upregulated in both cortex and hippocampus, whereas IL-1β, IL-6 and CCL2 were upregulated in the olfactory bulb. Furtherly, inhibiting microglia, rather than astrocytes, alleviated depression-like behaviors and dysosmia induced by E protein. Finally, RT-PCR and immunohistochemistry suggested that TLR2 was upregulated in the cortex, hippocampus and olfactory bulb, the blocking of which mitigated depression-like behaviors and dysosmia induced by E protein.ConclusionsOur study demonstrates that envelope protein could directly induce depression-like behaviors, dysosmia, and obvious neuroinflammation in CNS. TLR2 mediated depression-like behaviors and dysosmia induced by envelope protein, which could serve as a promising therapeutic target for neurological manifestation in COVID-19 patients.

Eradication of human immunodeficiency virus-1 reservoir in the brain microglia.

Eradication of human immunodeficiency virus-1 reservoir in the brain microglia.

Putting PLX5622 into perspective: microglia in central nervous system viral infection.

Putting PLX5622 into perspective: microglia in central nervous system viral infection.

PROTEOSTASIS: NOVEL INSIGHTS AND TECHNOLOGIES

Abstract Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. We derived cTFEB;HSA-Cre transgenic mice in the P301S MAPT background and we detected a significant reduction in hyperphosphorylated tau[AT8 phospho-tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefit sin P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise-associated neurotrophic signaling and reduced markers of advancing tau-associated pathologies in the hippocampus. These provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise-associated signaling in the CNS.

Exercise‐Associated Signaling Reduces Tau Accumulation and Neuroinflammation in P301S MAPT Transgenic Mice

AbstractBackgroundSkeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism‐modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise.MethodWe have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E‐B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. To directly test the potential neuroprotective effectsof enhancing skeletal muscle proteostasisin AD‐associated pathologies, we derived cTFEB;HSA‐Cre transgenic mice in the P301S MAPT background. This is a well‐characterized model of fronto‐temporal dementia and neurofibrillary tangle toxicity and has been previously shown to benefit from exercise interventions.ResultWe detected a significant reduction in the accumulation of hyperphosphorylated tau [AT8 phospho‐tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefits in P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise‐associated neurotrophic signaling and reduced markers of advancing tau‐associated pathologies in the hippocampus.ConclusionThese provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise‐associated signaling in the CNS.

Anti-inflammatory effects of siponimod on astrocytes

Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P1) and an agonist of S1P5. S1P1 antagonization, which inhibits lymphocyte egress from lymphoid tissues and subsequent infiltration into the central nervous system (CNS), is considered the main therapeutic mechanism of siponimod. In addition, siponimod’s direct effects on CNS glial cells are another potential neuroprotective mechanism because siponimod can penetrate the blood–brain barrier and CNS glial cells express S1P receptors. However, it remains uncertain whether siponimod directly affects CNS glial cells. In this study, we investigated siponimod’s effects on astrocytes using mouse primary cultures. Siponimod suppressed nuclear factor kappa B activation and pro-inflammatory cytokine production. Using antagonists for S1P1 and S1P5, we found that siponimod partially exerts its anti-inflammatory effects via S1P1, but not via S1P5. Moreover, siponimod also inhibited histone deacetylase, suggesting that siponimod exerts broad anti-inflammatory effects via S1P1 antagonization and histone deacetylase inhibition. Siponimod might suppress disease progression in multiple sclerosis in part via direct inhibition of astroglial CNS neuroinflammation.

Integrating Lipidomics and Transcriptomics Reveals the Crosstalk Between Oxidative Stress and Neuroinflammation in Central Nervous System Demyelination.

Multiple sclerosis (MS) is an incurable and progressive neurodegenerative disease that affects more than 2.5 million people worldwide and brings tremendous economic pressures to society. However, the pathophysiology of MS is still not fully elucidated, and there is no effective treatment. Demyelination is thought to be the primary pathophysiological alteration in MS, and our previous study found abnormal lipid metabolism in the demyelinated corpus callosum. Growing evidence indicates that central nervous system (CNS) demyelinating diseases never result from one independent factor, and the simultaneous participation of abnormal lipid metabolism, oxidative stress, and neuroinflammation could potentiate each other in the pathogenesis of MS. Therefore, a single omics analysis cannot provide a full description of any neurodegenerative disease. It has been demonstrated that oxidative stress and neuroinflammation are two reciprocal causative reasons for the progression of MS disease. However, the potential crosstalk between oxidative stress and neuroinflammation remains elusive so far. With an integrated analysis of targeted lipidomics and transcriptomics, our research presents the potential interaction between abnormalities of lipid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in CNS demyelinating diseases. The findings of this paper may be used to identify possible targets for the therapy of CNS demyelinating diseases.

The Bidirectional Signal Communication of Microbiota-Gut-Brain Axis in Hypertension.

Hypertension is a critical risk factor of cardiovascular diseases. A new concept of microbiota-gut-brain axis has been established recently, mediating the bidirectional communication between the gut and its microbiome and the brain. Alterations in bidirectional interactions are believed to be involved in the blood pressure regulation. Neuroinflammation and increased sympathetic outflow act as the descending innervation signals from the brain. Increased sympathetic activation plays a recognized role in the genesis of hypertension. The present evidence demonstrates that gut dysbiosis is associated with central nervous system neuroinflammation. However, how the gut influences the brain remains unclear. We reviewed the roles of neuroinflammation and gut microbiota and their interactions in the pathogenesis of hypertension and described the ascending signaling mechanisms behind the microbiota-gut-brain axis in detail. Additionally, the innovative prohypertensive mechanisms of dietary salt through the microbiota-gut-brain axis are summarized. The bidirectional communication mechanisms were proposed for the first time that the descending signals from the brain and the ascending connections from the gut form a vicious circle of hypertension progression, acting as a premise for hypertension therapy.

Developmental exposure to environmental levels of cadmium induces neurotoxicity and activates microglia in zebrafish larvae: From the perspectives of neurobehavior and neuroimaging

Cadmium (Cd) is a worldwide environmental pollutant that postures serious threats to humans and ecosystems. Over the years, its adverse effects on the central nervous system (CNS) have been concerned, whereas the underlying cellular/molecular mechanisms remain unclear. In this study, taking advantages of zebrafish model in high-throughput imaging and behavioral tests, we have explored the potential developmental neurotoxicity of Cd at environmentally relevant levels, from the perspectives of neurobehavior and neuroimaging. Briefly, Cd2+ exposure resulted in a general impairment of zebrafish early development. Zebrafish neurobehavioral patterns including locomotion and reactivity to environmental signals were significantly perturbed upon Cd2+ exposure. Importantly, a combination of in vivo two-photon neuroimaging, flow cytometry and gene expression analyses revealed notable neurodevelopmental disorders as well as neuroimmune responses induced by Cd2+ exposure. Both cell-cycle arrest and apoptosis contributed jointly to a significant decrease of neuronal density in zebrafish larvae exposed to Cd2+. The dramatic morphological alterations of microglia from multi-branched to amoeboid, the microgliosis, as well as the modulation of gene expression profiles demonstrated a strong activation of microglia and neuroinflammation triggered by environmental levels of Cd2+. Together, our study points to the developmental toxicity of Cd in inducing CNS impairment and neuroinflammation thereby providing visualized etiological evidence of this heavy metal induced neurodevelopmental disorders. It's tempting to speculate that this research model might represent a promising tool not only for understanding the molecular mechanisms of Cd-induced neurotoxicity, but also for developing pharmacotherapies to mitigate the neurological damage resulting from exposure to Cd, and other neurotoxicants.

PDCD4 Simultaneously Promotes Microglia Activation via PDCD4-MAPK-NF-κB Positive Loop and Facilitates Neuron Apoptosis During Neuroinflammation.

Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared key regulatory molecules and thus explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic proteins BAX and Cleaved-PARP, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4-MAPK-NF-κB positive feedback loop may act as pivotal signaling for neuroinflammation which subsequently exaggerates neuronal injury, and thus may become a potential therapeutic target for neuroinflammatory diseases.

Scutellarin alleviates depression-like behaviors induced by LPS in mice partially through inhibition of astrocyte-mediated neuroinflammation

Depression is a kind of common mental disorder associated with neuroinflammation, and astrocytes play a vital role in regulating and mediating neuroinflammation in central nervous system. Scutellarin has significant anti-inflammatory and neuroprotective effects. However, whether scutellarin exerts antidepressant effect remains unknown. In present study, it was found that scutellarin suppressed LPS-induced neuroinflammation in the hippocampus and alleviated depression-like behaviors in mice. In addition, scutellarin inhibited LPS-induced elevation of TNFα, IL-1β, IL-6 and iNOS, and reversed the downregulation of IL-4 and BDNF in astrocytes in vitro. Furthermore, the activated TLR4/NF-κB pathway in LPS-treated astrocytes was suppressed by scutellarin. Collectively, these results suggest that scutellarin ameliorates depression-like behaviors induced by neuroinflammation partially through inhibiting the TLR4/NF-κB pathway in astrocytes.

Scorpion Venom Heat-Resistant Peptide Attenuates Microglia Activation and Neuroinflammation.

Background: Intervention of neuroinflammation in central nervous system (CNS) represents a potential therapeutic strategy for a host of brain disorders. The scorpion Buthus martensii Karsch (BmK) and its venom have long been used in the Orient to treat inflammation-related diseases such as rhumatoid arthritis and chronic pain. Scorpion venom heat-resistant peptide (SVHRP), a component from BmK venom, has been shown to reduce seizure susceptibility in a rat epileptic model and protect against cerebral ischemia-reperfusion injury. As neuroinflammation has been implicated in chronic neuronal hyperexcitability, epileptogenesis and cerebral ischemia-reperfusion injury, the present study aimed to investigate whether SVHRP has anti-inflammatory property in brain. Methods: An animal model of neuroinflammation induced by lipopolysacchride (LPS) injection was employed to investigate the effect of SVHRP (125 µg/kg, intraperitoneal injection) on inflammagen-induced expression of pro-inflammatory factors and microglia activation. The effect of SVHRP (2–20 μg/ml) on neuroinflammation was further investigated in primary brain cell cultures containing microglia as well as the immortalized BV2 microglia culture stimulated with LPS. Real-time quantitative PCR were used to measure mRNA levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in hippocampus of animals. Protein levels of TNF-α, iNOS, P65 subunit of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) were examined by ELISA or western blot. Microglia morphology in animal hippocampus or cell cultures and cellular distribution of p65 were shown by immunostaining. Results: Morphological study demonstrated that activation of microglia, the main component that mediates the neuroinflammatory process, was inhibited by SVHRP in both LPS mouse and cellular model. Our results also showed dramatic increases in the expression of iNOS and TNF-α in hippocampus of LPS-injected mice, which was significantly attenuated by SVHRP treatment. In vitro results showed that SVHRP attenuated LPS-elicited expression of iNOS and TNF-α in different cultures without cell toxicity, which might be attributed to suppression of NF-κB and MAPK pathways by SVHRP. Conclusion: Our study demonstrates that SVHRP is able to inhibit neuroinflammation and microglia activation, which may underlie the therapeutic effects of BmK-derived materials, suggesting that BmK venom could be a potential source for CNS drug development.

Inhibition of P2X4R attenuates white matter injury in mice after intracerebral hemorrhage by regulating microglial phenotypes

BackgroundWhite matter injury (WMI) is a major neuropathological event associated with intracerebral hemorrhage (ICH). P2X purinoreceptor 4 (P2X4R) is a member of the P2X purine receptor family, which plays a crucial role in regulating WMI and neuroinflammation in central nervous system (CNS) diseases. Our study investigated the role of P2X4R in the WMI and the inflammatory response in mice, as well as the possible mechanism of action after ICH.MethodsICH was induced in mice via collagenase injection. Mice were treated with 5-BDBD and ANA-12 to inhibit P2X4R and tropomyosin-related kinase receptor B (TrkB), respectively. Immunostaining and quantitative polymerase chain reaction (qPCR) were performed to detect microglial phenotypes after the inhibition of P2X4R. Western blots (WB) and immunostaining were used to examine WMI and the underlying molecular mechanisms. Cylinder, corner turn, wire hanging, and forelimb placement tests were conducted to evaluate neurobehavioral function.ResultsAfter ICH, the protein levels of P2X4R were upregulated, especially on day 7 after ICH, and were mainly located in the microglia. The inhibition of P2X4R via 5-BDBD promoted neurofunctional recovery after ICH as well as the transformation of the pro-inflammatory microglia induced by ICH into an anti-inflammatory phenotype, and attenuated ICH-induced WMI. Furthermore, we found that TrkB blockage can reverse the protective effects of WMI as well as neuroprotection after 5-BDBD treatment. This result indicates that P2X4R plays a crucial role in regulating WMI and neuroinflammation and that P2X4R inhibition may benefit patients with ICH.ConclusionsOur results demonstrated that P2X4R contributes to WMI by polarizing microglia into a pro-inflammatory phenotype after ICH. Furthermore, the inhibition of P2X4R promoted pro-inflammatory microglia polarization into an anti-inflammatory phenotype, enhanced brain-derived neurotrophic factor (BDNF) production, and through the BDNF/TrkB pathway, attenuated WMI and improved neurological function. Therefore, the regulation of P2X4R activation may be beneficial for the reducing of ICH-induced brain injury.

Getting around the blood–brain barrier

Neuroimmunology The meninges comprise three membranes that surround and protect the central nervous system (CNS). Recent studies have noted the existence of myeloid cells resident there, but little is known about their ontogeny and function, and whether other meningeal immune cell populations have important roles remains unclear (see the Perspective by Nguyen and Kubes). Cugurra et al. found in mice that a large proportion of continuously replenished myeloid cells in the dura mater are not blood derived, but rather transit from cranial bone marrow through specialized channels. In models of CNS injury and neuroinflammation, the authors demonstrated that these myeloid cells have an immunoregulatory phenotype compared with their more inflammatory blood-derived counterparts. Similarly, Brioschi et al. show that the meninges host B cells that are also derived from skull bone marrow, mature locally, and likely acquire a tolerogenic phenotype. They further found that the brains of aging mice are infiltrated by a second population of age-associated B cells, which come from the periphery and may differentiate into autoantibody-secreting plasma cells after encountering CNS antigens. Together, these two studies may inform future treatment of neurological diseases. Science , abf7844, abf9277, this issue p. [eabf7844][1], p. [eabf9277][2]; see also abj8183, p. [396][3] [1]: /lookup/doi/10.1126/science.abf7844 [2]: /lookup/doi/10.1126/science.abf9277 [3]: /lookup/doi/10.1126/science.abj8183

Global research trends of Apolipoprotein E in central nervous system: A scientometric analysis

Apolipoprotein E (apoE, protein; APOE, gene) involves in cholesterol recycling and redistribution by mediating lipoprotein pathways unique to central nervous system (CNS), which is a potential therapeutic target for diseases. We visually analyzed the research hotspots of APOE related to CNS in this work, by scientometric analysis from the Web of Science Core Collection (WOSCC) database over the past two decades. A total of 25,719 references of “APOE” and 836 references of “APOE in CNS” were retrieved from the WOSCC on October 26, 2020, and then VOSviewer 1.6.15, Citespace 5.7.R2 were used for visual analysis. Over the last two decades, the research on the field of APOE in CNS is not faddish. Although many funds, organizations, and scholars were affiliated in this field, organizations and scholars, especially the top teams in this field, still lacked close cooperation with other teams around the world. Few articles with high citations had been published in the last decade, but recent studies still lacked scale and breakthrough, and the keywords associated with APOE appeared more outdated. However, the current researches have not fully elucidated the crosstalk between APOE and neuroinflammation in CNS, some new ideas may rekindle the research enthusiasm of scholars. Although the field of APOE in CNS appeared more outdated. Based on keyword analysis, we hypothesized new ideas for further investigation of neuroinflammation would light the interest of APOE in CNS for the scholars. The crosstalk between ApoE and inflammasome may be the focus of future researches. How APOE modulates the time course or intensity of the inflammasome activation, inflammatory response (proinflammatory or anti-inflammatory), and pathological process of CNS disease deserves future attention in both basic and clinical studies. More apoE/APOE-targeted pharmacological interventions will be available for preclinical experiments and clinical trials and bring hope for patients with CNS diseases.

Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders

The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells. which may help maintain immune privilege within the CNS.