小胶质细胞在病毒性中枢神经系统感染中的作用

小胶质细胞是中枢神经系统中的免疫细胞,是中枢神经系统抵抗病原体入侵的第一道防线。当病原微生物进入脑组织后,小胶质细胞迅速做出反应,识别、吞噬病原微生物,呈递抗原和分泌多种生物活性物质。但是,小胶质细胞的过度活化又可诱发中枢神经系统免疫病理损伤或神经退行性病变。因而,具有生理和病理双重作用。本文就小胶质细胞在病毒感染性中枢神经系统疾病中的作用及其机制进行综述。     

胶质微环境与中枢神经系统损伤修复

中枢神经系统(central mervous system,CNS)损伤包括腩损伤和脊髓损伤,致残率和病死率较高.因此,CNS损伤修复一直是神经科学领域的一个研究重点和热点.成年哺乳动物神经元的内在再生能力有限是CNS损伤后再生困难的原因之一,但更为重要的原因是损伤局部抑制性胶质微环境的形成.文章就胶质微环境内星形胶质细胞、小胶质细胞、少突胶质细胞等各类组成细胞在CNS损伤修复中的作用做了综述.     

Protective effects of naloxone in two‐hit seizure model

Purpose: Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two‐hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose‐dependent protective effects of naloxone in kainic acid (KA)–induced two‐hit seizure model. Methods: After KA‐induced SE at postnatal day 15 (P15), Sprague‐Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin‐1β [IL‐1β], S100B) was assessed by real‐time polymerase chain reaction (PCR) and enzyme‐linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT‐mediated dUTP nick end labeling (TUNEL) assays. Results: Naloxone reduced IL‐1β synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions: Naloxone treatment immediately after early life SE could dose‐dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood.     

Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia?

Chronic psychosocial stress is increasingly recognized as a risk factor for late-onset Alzheimer's disease (LOAD) and associated cognitive deficits. Chronic stress also primes microglia and induces inflammatory responses in the adult brain, thereby compromising synapse-supportive roles of microglia and deteriorating cognitive functions during aging. Substantial evidence demonstrates that failure of microglia to clear abnormally accumulating amyloid-beta (Aβ) peptide contributes to neuroinflammation and neurodegeneration in AD. Moreover, genome-wide association studies have linked variants in several immune genes, such as TREM2 and CD33, the expression of which in the brain is restricted to microglia, with cognitive dysfunctions in LOAD. Thus, inflammation-promoting chronic stress may create a vicious cycle of aggravated microglial dysfunction accompanied by increased Aβ accumulation, collectively exacerbating neurodegeneration. Surprisingly, however, little is known about whether and how chronic stress contributes to microglia-mediated neuroinflammation that may underlie cognitive impairments in AD. This review aims to summarize the currently available clinical and preclinical data and outline potential molecular mechanisms linking stress, microglia and neurodegeneration, to foster future research in this field.     

Chronic ethanol intake induces partial microglial activation that is not reversed by long-term ethanol withdrawal in the rat hippocampal formation

Neuroinflammation has been implicated in the pathogenesis of several disorders. Activation of microglia leads to the release of pro-inflammatory mediators and microglial-mediated neuroinflammation has been proposed as one of the alcohol-induced neuropathological mechanisms. The present study aimed to examine the effect of chronic ethanol exposure and long-term withdrawal on microglial activation and neuroinflammation in the hippocampal formation. Male rats were submitted to 6 months of ethanol treatment followed by a 2-month withdrawal period. Stereological methods were applied to estimate the total number of microglia and activated microglia detected by CD11b immunohistochemistry in the hippocampal formation. The expression levels of the pro-inflammatory cytokines TNF-α, COX-2 and IL-15 were measured by qRT-PCR. Alcohol consumption was associated with an increase in the total number of activated microglia but morphological assessment indicated that microglia did not exhibit a full activation phenotype. These data were supported by functional evidence since chronic alcohol consumption produced no changes in the expression of TNF-α or COX-2. The levels of IL-15 a cytokine whose expression is increased upon activation of both astrocytes and microglia, was induced by chronic alcohol treatment. Importantly, the partial activation of microglia induced by ethanol was not reversed by long-term withdrawal. This study suggests that chronic alcohol exposure induces a microglial phenotype consistent with partial activation without significant increase in classical cytokine markers of neuroinflammation in the hippocampal formation. Furthermore, long-term cessation of alcohol intake is not sufficient to alter the microglial partial activation phenotype induced by ethanol.     

Brain trauma induces expression of diacylglycerol kinase ζ in microglia

Diacylglycerol kinase (DGK) is an enzyme which phosphorylates a second messenger diacylglycerol and consists of a family of isozymes that differ in terms of structural motifs, enzymological property, and cell and tissue distribution. One of the isozymes, DGKζ was originally shown to be expressed in various kinds of neurons under physiological conditions. However, we unexpectedly found that under pathological conditions, such as cerebral infarction, DGKζ-immunoreactivity is detected in non-neuronal cells, although it remained to be elucidated in detail which cell types are responsible for the induced expression of DGKζ in this setting. To further elucidate functional implications of DGKζ in non-neuronal cells we performed detailed immunohistochemical analysis of DGKζ using rat brain cryoinjury model. As early as 1 h after cryoinjury, DGKζ-immunoreactivity was greatly decreased in the afflicted cerebral cortex and almost disappeared in the necrotic core. On day 7 after cryoinjury, however, DGKζ-immunoreactivity reappeared in this area. DGKζ-immunoreactivity was clearly detected in Iba1-immunoreactive cells of an oval or ameboid shape in the scar region, which represent activated microglia and/or macrophages. On the other hand, DGKζ-immunoreactivity was not detected in Iba1-immunoreactive, resting microglia of ramified and dendritic configuration in the intact cortex. Furthermore, DGKζ-immunoreactive cells were also positive for a microglia marker GLUT5 in the scar region, but never for an astrocyte marker GFAP. Taken together, the present study reveals that DGKζ is induced in activated microglia in brain trauma, suggesting the functional significance of DGKζ in this process.     

Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus

The hippocampus is insensitive to strong inflammatory stimulus under normal conditions and one of the most severely affected areas in Alzheimer's disease. We have analyzed the effect of chronic stress for 9 days in the hippocampus unilaterally injected with LPS. In non-stressed rats, LPS injection failed to activate microglia although a subset of degenerating cells in the CA1 area was evident. This effect was not accompanied by loss of Neu-N positive neurons in the CA1 area. In stressed rats, LPS injection had a dramatic effect in activating microglia along with astrogliosis and BDNF mRNA induction. NeuN immunostaining demonstrated a loss of about 50% of CA1 pyramidal neurons under these conditions. Fluoro jade B histochemistry demonstrated the presence of degenerating cells in most of CA1 area. Mechanistically, combination of chronic stress and LPS resulted in prominent activation of MAPKs including JNK, p38 and ERK clearly different from LPS injection in controls. Further, LPS + stress induced a dramatic decrease in phosphorylated levels of both Akt and CREB, which fully supports a consistent deleterious state in the hippocampal system under these conditions. Treatment with RU486, a potent inhibitor of glucocorticoid receptor activation, significantly protected animals against the deleterious effects observed in LPS-stressed animals.     

White matter neuron alterations in schizophrenia and related disorders

Increased density and altered spatial distribution of subcortical white matter neurons (WMNs) represents one of the more well replicated cellular alterations found in schizophrenia and related disease. In many of the affected cases, the underlying genetic risk architecture for these WMN abnormalities remains unknown. Increased density of neurons immunoreactive for Microtubule-Associated Protein 2 (MAP2) and Neuronal Nuclear Antigen (NeuN) have been reported by independent studies, though there are negative reports as well; additionally, group differences in some of the studies appear to be driven by a small subset of cases. Alterations in markers for inhibitory (GABAergic) neurons have also been described. For example, downregulation of neuropeptide Y (NPY) and nitric oxide synthase (NOS1) in inhibitory WMN positioned at the gray/white matter border, as well as altered spatial distribution, have been reported. While increased density of WMN has been suggested to reflect disturbance of neurodevelopmental processes, including neuronal migration, neurogenesis, and cell death, alternative hypotheses—such as an adaptive response to microglial activation in mature CNS, as has been described in multiple sclerosis -should also be considered. We argue that larger scale studies involving hundreds of postmortem specimens will be necessary in order to clearly establish the subset of subjects affected. Additionally, these larger cohorts could make it feasible to connect the cellular pathology to environmental and genetic factors implicated in schizophrenia, bipolar disorder, and autism. These could include the 22q11 deletion (Velocardiofacial/DiGeorge) syndrome, which in some cases is associated with neuronal ectopias in white matter.     

Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge

Acute and chronic stressors sensitize or prime the neuroinflammatory response to a subsequent peripheral or central immunologic challenge. However, the neuroimmune process(es) by which stressors prime or sensitize subsequent neuroinflammatory responses remains unclear. Prior evidence suggested that toll-like receptors (TLRs) might be involved in the mediation of primed neuroinflammatory responses, but the role of TLRs during a stressor has never been directly tested. Here, a novel TLR2 and TLR4 antagonist, OxPAPC, was used to probe the contribution of TLRs in the stress sensitization phenomenon. OxPAPC has not previously been administered to the brain, and so its action in blocking TLR2 and TLR4 action in brain was first verified. Administration of OxPAPC into the CNS prior to stress prevented the stress-induced potentiation of hippocampal pro-inflammatory response to a subsequent peripheral LPS challenge occurring 24 h later. In addition, in vivo administration of OxPAPC prior to stress prevented the sensitized pro-inflammatory response from isolated microglia following administration of LPS ex vivo, further implicating microglia as a key neuroimmune substrate that mediates stress-induced sensitized neuroinflammation.