Microglia: Housekeeper of the Central Nervous System

Microglia, of myeloid origin, play fundamental roles in the control of immune responses and the maintenance of central nervous system homeostasis. These cells, just like peripheral macrophages, may be activated into M1 pro-inflammatory or M2 anti-inflammatory phenotypes by appropriate stimuli. Microglia do not respond in isolation, but form part of complex networks of cells influencing each other. This review addresses the complex interaction of microglia with each cell type in the brain: neurons, astrocytes, cerebrovascular endothelial cells, and oligodendrocytes. We also highlight the participation of microglia in the maintenance of homeostasis in the brain, and their roles in the development and progression of age-related neurodegenerative disorders.     

Microglia Function in Central Nervous System Development and Plasticity

The nervous system comprises a remarkably diverse and complex network of different cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in the spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS and highlight exciting new work in the field that has identified roles for these cells in CNS development, maintenance, and plasticity.Microglia are one of the most enigmatic and understudied populations in the brain. Until recently, most of what was known about their function has been associated with their rapid and robust responses to disease and injury (Ransohoff and Perry 2009; Graeber 2010; Ransohoff and Cardona 2010). The idea that microglia could be performing normal, homeostatic functions is a relatively new concept, galvanized by pioneering in vivo imaging studies, which revealed that the processes of “resting” microglia are highly motile in the intact, healthy adult brain (Davalos et al. 2005; Nimmerjahn et al. 2005). Remarkably, it is estimated that these microglial processes survey the entire brain parenchyma within a matter of hours, raising many questions about the significance of this immune surveillance system.Since these initial findings, there has been a surge in the field to examine functional roles of microglia in the healthy central nervous system (CNS), with a primary focus on postnatal development. This focus was, to a large extent, incited by a landmark fate-mapping study in the mouse showing that microglia develop from primitive myeloid progenitors in the embryonic yolk sac and begin to colonize the brain during early embryonic development (approximately embryonic day 9.5 [∼E9.5] in the mouse) (Ginhoux et al. 2010). Given this early colonization, microglia are poised to play important roles in shaping the developing CNS and contributing to overall nervous system function. Indeed, recent work has shown that microglia in the developing CNS can physically interact with neuronal soma and synapses in response to changes in neural activity, and data implicate microglia in many functions required to build and wire the developing CNS ranging from neurogenesis to synaptic pruning (Tremblay 2011; Tremblay et al. 2011; Kettenmann et al. 2013; Schafer et al. 2013; Wake et al. 2013; Salter and Beggs 2014). Furthermore, emerging work in the juvenile and adult reveal that these interactions and functions observed in the postnatal brain occur more broadly to affect plasticity over the life span of the animal, ultimately affecting behavior.In this chapter, we review the latest findings in the field on microglia function in CNS development and plasticity. Our goal is to give a comprehensive and critical perspective of this relatively new area of research and highlight new questions. Furthermore, we discuss novel strategies to manipulate microglia function that will contribute to our understanding of these cells in the healthy nervous system and, ultimately, help to identify mechanisms of disease.     

Culturing Microglia from the Neonatal and Adult Central Nervous System

Microglia are the resident macrophage-like cells of the central nervous system (CNS) and, as such, have critically important roles in physiological and pathological processes such as CNS maturation in development, multiple sclerosis, and spinal cord injury. Microglia can be activated and recruited to action by neuronal injury or stimulation, such as axonal damage seen in MS or ischemic brain trauma resulting from stroke. These immunocompetent members of the CNS are also thought to have roles in synaptic plasticity under non-pathological conditions. We employ protocols for culturing microglia from the neonatal and adult tissues that are aimed to maximize the viable cell numbers while minimizing confounding variables, such as the presence of other CNS cell types and cell culture debris. We utilize large and easily discernable CNS components (e.g. cortex, spinal cord segments), which makes the entire process feasible and reproducible. The use of adult cells is a suitable alternative to the use of neonatal brain microglia, as many pathologies studied mainly affect the postnatal spinal cord. These culture systems are also useful for directly testing the effect of compounds that may either inhibit or promote microglial activation. Since microglial activation can shape the outcomes of disease in the adult CNS, there is a need for in vitro systems in which neonatal and adult microglia can be cultured and studied.     

溶酶体组织蛋白酶D与中枢神经系统疾病

组织蛋白酶D(cathepsinD,carD)是溶酶体内天门冬氨酸蛋白内切酶,广泛分布于人体组织,在脑组织中则主要定位于神经元和脉络丛上皮细胞,其表达、分布及活性的变化影响着中枢神经系统疾病的发生发展,而平衡catD表达与活性及稳定其基因多态性有利于减少疾病发展的风险.在早期的研究中,catD的功能主要与乳腺癌的浸润和转移有关,而后将其作为雌激素依赖的肿瘤标志物来观察.但近几年的研究发现其在神经元的损伤中发挥着重要作用,说明catD与神经系统疾病也有着非常重要的关系.     

The Role of Microglia in the Homeostasis of the Central Nervous System and Neuroinflammation

Molecular Biology - Recently, much attention has been drawn to unraveling the mechanisms of neurodegenerative and neuroinflammatory disease pathogenesis. A special role in the development of...     

HMGB1 in Development and Diseases of the Central Nervous System

High mobility group box 1 (HMGB1) is widely expressed in cells of vertebrates in two forms: a nuclear "architectural" factor and a secreted inflammatory factor. During early brain development, HMGB1 displays a complex temporal and spatial distribution pattern in the central nervous system. It facilitates neurite outgrowth and cell migration critical for processes, such as forebrain development. During adulthood, HMGB1 serves to induce neuroinflammation after injury, such as lesions in the spinal cord and brain. Receptor for advanced glycation end products and Toll-like receptors signal transduction pathways mediate HMGB1-induced neuroinflammation and necrosis. Increased levels of endogenous HMGB1 have also been detected in neurodegenerative diseases. However, in Huntington's disease, HMGB1 has been reported to protect neurons through activation of apurinic/apyrimidinic endonuclease and 5'-flap endonuclease-1, whereas in other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, HMGB1 serves as a risk factor for memory impairment, chronic neurodegeneration, and progression of neuroinflammation. Thus, HMGB1 plays important and double-edged roles during neural development and neurodegeneration. The HMGB1-mediated pathological mechanisms have remained largely elusive. Knowledge of these mechanisms is likely to lead to therapeutic targets for neurological diseases.     

Cerebrospinal Fluid Interleukin-6 in Central Nervous System Inflammatory Diseases

Background

Interleukin (IL)-6 is recognised as an important cytokine involved in inflammatory diseases of the central nervous system (CNS).

Objective

To perform a large retrospective study designed to test cerebrospinal fluid (CSF) IL-6 levels in the context of neurological diseases, and evaluate its usefulness as a biomarker to help discriminate multiple sclerosis (MS) from other inflammatory neurological diseases (OIND).

Patients and Methods

We analyzed 374 CSF samples for IL-6 using a quantitative enzyme-linked immunosorbent assay. Groups tested were composed of demyelinating diseases of the CNS (DD, n = 117), including relapsing-remitting MS (RRMS, n = 65), primary progressive MS (PPMS, n = 11), clinically isolated syndrome (CIS, n = 11), optic neuritis (ON, n = 30); idiopathic transverse myelitis (ITM, n = 10); other inflammatory neurological diseases (OIND, n = 35); and non-inflammatory neurological diseases (NIND, n = 212). Differences between groups were analysed using Kruskal−Wallis test and Mann−Whitney U-test.

Results

CSF IL-6 levels exceeded the positivity cut-off of 10 pg/ml in 18 (51.4%) of the 35 OIND samples, but in only three (3.9%) of the 76 MS samples collected. CSF IL-6 was negative for all NIND samples tested (0/212). IL-6 cut-off of 10 pg/ml offers 96% sensitivity to exclude MS.

Conclusion

CSF IL-6 may help to differentiate MS from its major differential diagnosis group, OIND.     

Herpesvirus-Associated Central Nervous System Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ±1.9% and 4.1% ±1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19⁺CD20⁺ B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.     

Vimentin in the Central Nervous System

Intermediate filament proteins were identified by two-dimensional gel electrophoresis in urea extracts of rat optic nerves undergoing Wallerian degeneration and in cytoskeletal preparations of rat brain and spinal cord during postnatal development. The glial fibrillary acidic (GFA) protein and vimentin were the major optic nerve proteins following Wallerian degeneration. Vimentin was a major cytoskeletal component of newborn central nervous system (CNS) and then progressively decreased until it became barely identifiable in mature brain and spinal cord. The decrease of vimentin occurred concomitantly with an increase in GFA protein. A protein with the apparent molecular weight of 61,000 and isoelectric point of 5.6 was identified in both cytoskeletal preparations of brain and spinal cord, and in urea extracts of normal optic nerves. The protein disappeared together with the polypeptides forming the neurofilament triplet in degenerated optic nerves.     

The Role of Secretory Phospholipase A2 in the Central Nervous System and Neurological Diseases

Secretory phospholipase A₂ (sPLA₂s) are small secreted proteins (14–18 kDa) and require submillimolar levels of Ca²⁺ for liberating arachidonic acid from cell membrane lipids. In addition to the enzymatic function, sPLA₂ can exert various biological responses by binding to specific receptors. Physiologically, sPLA₂s play important roles on the neurotransmission in the central nervous system and the neuritogenesis in the peripheral nervous system. Pathologically, sPLA₂s are involved in the neurodegenerative diseases (e.g., Alzheimer’s disease) and cerebrovascular diseases (e.g., stoke). The common pathology (e.g., neuronal apoptosis) of Alzheimer’s disease and stroke coexists in the mixed dementia, suggesting common pathogenic mechanisms of the two neurological diseases. Among mammalian sPLA₂s, sPLA₂-IB and sPLA₂-IIA induce neuronal apoptosis in rat cortical neurons. The excess influx of calcium into neurons via l-type voltage-dependent Ca²⁺ channels mediates the two sPLA₂-induced apoptosis. The elevated concentration of intracellular calcium activates PKC, MAPK and cytosolic PLA₂. Moreover, it is linked with the production of reactive oxygen species and apoptosis through activation of the superoxide producing enzyme NADPH oxidase. NADPH oxidase is involved in the neurotoxicity of amyloid β peptide, which impairs synaptic plasticity long before its deposition in the form of amyloid plaques of Alzheimer’s disease. In turn, reactive oxygen species from NADPH oxidase can stimulate ERK1/2 phosphorylation and activation of cPLA₂ and result in a release of arachidonic acid. sPLA₂ is up-regulated in both Alzheimer’s disease and cerebrovascular disease, suggesting the involvement of sPLA₂ in the common pathogenic mechanisms of the two diseases. Thus, our review presents evidences for pathophysiological roles of sPLA₂ in the central nervous system and neurological diseases.     

乳酸在中枢神经系统中的作用及其与相关疾病的关系

一直以来,乳酸在脑中被视作代谢废物,对其功能认识严重滞后。近年来,越来越多的证据表明,乳酸在多种生理与病理过程中扮演重要角色。在神经细胞中,星形胶质细胞是产生和释放乳酸的主要细胞源,该细胞通过有氧糖酵解过程生成乳酸,随后经跨膜通道释放至胞外进入神经元为其供能。在中枢神经系统中,乳酸对稳态调节发挥着十分重要的作用。乳酸主要通过两种途径,即代谢途径(作为能量底物)与信号途径(作为信号分子)调控神经元的功能活动,广泛参与神经元能量代谢、兴奋性、可塑性、学习记忆及神经系统发育等生理过程调节,亦参与抑郁行为、阿尔兹海默病(AD)和脑损伤等病理过程的调节。在脑组织中,存在着乳酸特异性受体(GPR81),乳酸与其结合后调控胞内的第二信使。此外,还发现乳酸可通过未知受体调节神经元的兴奋性以及作为信号分子的其他作用。本文就乳酸作为能量底物和信号分子及其参与相关神经疾病的研究进展进行阐述,旨在为相关中枢神经系统疾病防治提供新思路。