Inflammation in Traumatic Brain Injury: Role of Cytokines and Chemokines

A traumatic injury to the adult mammalian central nervous system (CNS), such as a stab wound lesion, results in reactive astrogliosis and the migration of hematogenous cells into the damaged neural tissue. The roles of cytokines and growth factors released locally by the damaged endogenous cells are recognized in controlling the cellular changes that occur following CNS injury. However, the role of chemokines, a novel class of chemoattractant cytokines, is only recently being studied in regulating inflammatory cell invasion in the injured/diseased CNS (1). The mRNAs for several chemokines have been shown to be upregulated in experimental allergic encephalomyelitis (EAE), an inflammatory demyelinating disease of the CNS, but chemokine expression in traumatic brain injury has not been studied in detail. Astrocytes have been demonstrated to participate in numerous processes that occur following injury to the CNS. In particular, astrocytic expression of cytokines and growth factors in the injured CNS has been well reviewed (2). Recently a few studies have detected the presence of chemokines in astrocytes following traumatic brain injury (3,4). These studies have suggested that chemokines may represent a promising target for future therapy of inflammatory conditions. This review summarizes the events that occur in traumatic brain injury and discusses the roles of resident and non-resident cells in the expression of growth factors, cytokines and chemokines in the injured CNS.     

Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury.This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation.     

Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response

TNF-α has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-α strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-1β or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF-α antagonist etanercept to discover whether hepatic TNF-α, produced as part of the acute-phase response to CNS injury, modulates the inflammatory response in the brain. We report a significant reduction in neutrophil numbers recruited to the IL-1β- or LPS-challenged brain as a result of TNF-α inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF-α mRNA and of TNF-α-induced genes, such as the chemokines CCL-2, CXCL-5, and CXCL-10, although other chemokines elevated by the injury were not significantly changed. The reduction in hepatic chemokine synthesis results in reduced numbers of circulating neutrophils, and also a reduction in the numbers recruited to the liver as a consequence of brain injury. These findings suggest that TNF-α inhibitors may reduce CNS inflammatory responses by targeting the hepatic acute-phase response, and thus therapies for brain injury need not cross the blood–brain barrier to be effective.     

单细胞转录组测序在药物成瘾研究中的应用

药物成瘾是复杂的中枢神经系统疾病，相关基础与临床研究均证实药物成瘾的神经机制及神经环路在成瘾行为形成的不同阶段逐渐发生改变。利用全基因组关联研究、全基因组测序、全外显子测序或高通量转录组测序等技术的组学研究对包括药物成瘾在内的精神疾病遗传的脆弱性进行了深入研究。上述单核苷酸多态性检测技术或测序技术主要预测疾病的遗传风险位点。然而，许多中枢神经系统疾病的发生与环境因素密切相关，而且在疾病发展的不同阶段，相关基因的表达存在脑区特异性的细胞异质性信息。因此，传统研究对发病机制的解释存在一定的局限性。单细胞转录组测序技术是针对单个细胞进行转录水平的测定，规避了传统测序对细胞群体平均转录水平检测的缺点，可以定量描述细胞异质性。近年来，单细胞转录测序技术在神经精神科学研究中的应用逐渐受到关注，本文总结了该技术在神经科学研究中的重要应用，并以药物成瘾为例，重点阐述说明其在中枢神经系统疾病中的应用价值。     

Modeling of microstructural kinematics during simple elongation of central nervous system tissue

Damage to axons and glial cells in the central nervous system (CNS) white matter is a nearly universal feature of traumatic brain injury, yet it is not clear how the tissue mechanical deformations are transferred to the cellular components of the CNS. Defining how cellular deformations relate to the applied tissue deformation field can both highlight cellular populations at risk for mechanical injury, and define the fraction of cells in a specific population that will exhibit damage. In this investigation, microstructurally based models of CNS white matter were developed and tested against measured transformations of the CNS tissue microstructure under simple elongation. Results show that axons in the unstretched optic nerves were significantly wavy or undulated, where the measured axonal path length was greater than the end-to-end distance of the axon. The average undulation parameter--defined as the true axonal length divided by the end-to-end length--was 1.13. In stretched nerves, mean axonal undulations decreased with increasing applied stretch ratio (lambda)--the mean undulation values decreased to 1.06 at lambda = 1.06, 1.04 at lambda = 1.12, and 1.02 at lambda = 1.25. A model describing the gradual coupling, or tethering, of the axons to the surrounding glial cells best fit the experimental data. These modeling efforts indicate the fraction of the axonal and glial populations experiencing deformation increases with applied elongation, consistent with the observation that both axonal and glial cell injury increases at higher levels of white matter injury. Ultimately, these results can be used in conjunction with computational simulations of traumatic brain injury to aid in establishing the relative risk of cellular structures in the CNS white matter to mechanical injury.     

Protective roles of melatonin in central nervous system diseases by regulation of neural stem cells

Neural stem cells (NSCs) are immature precursors of the central nervous system (CNS), with self‐renewal and multipotential differentiation abilities. Their proliferation and differentiation are dynamically regulated by hormonal and local factors. Alteration in neurogenesis is associated with many neurological disorders. Increasing evidence suggests that modulation of NSCs can be a promising therapeutic approach for neural injury and neurodegenerative disorders. Melatonin, a pineal gland‐derived hormone, regulates the neuroimmuno‐endocrine axis and is functionally important to the circadian rhythm, tumour suppression and immunity. In the CNS, melatonin exerts neuroprotective effects in many diseases, such as Parkinson's disease, Alzheimer's disease and ischaemic brain injury. Emerging evidence suggests that it might also mediate such protective action by influencing proliferation and differentiation of NSCs. In this article, we review the current literature concerned with effects of melatonin on NSCs in different physiological and pathological conditions.     

Adult stem cells and bioengineering strategies for the treatment of cerebral ischemic stroke

The adult central nervous system (CNS) contains a population of neural stem cells, yet unlike many other tissues, has a very limited capacity for self-repair. Promoting tissue repair and functional recovery following CNS injury or disease is a high priority as there are currently no effective treatments towards this end for the treatment of disorders such as stroke, traumatic brain injury and spinal cord injury. Recent advances in stem cell biology have offered a number of enticing potential avenues and we will discuss these possibilities along with the associated challenges as they pertain to stroke. We will consider exogenous therapies involving the transplantation of adult stem cells, and the mobilization of endogenous stem cells, as well as drug delivery and tissue engineering strategies that enhance and complement the cell based strategies.     

Cardiolipin in Central Nervous System Physiology and Pathology

Cardiolipin, an anionic phospholipid found primarily in the inner mitochondrial membrane, has many well-defined roles within the peripheral tissues, including the maintenance of mitochondrial membrane fluidity and the regulation of mitochondrial functions. Within the central nervous system (CNS), cardiolipin is found within both neuronal and non-neuronal glial cells, where it regulates metabolic processes, supports mitochondrial functions, and promotes brain cell viability. Furthermore, cardiolipin has been shown to act as an elimination signal and participate in programmed cell death by apoptosis of both neurons and glia. Since cardiolipin is associated with regulating brain homeostasis, the modification of its structure, or even a decrease in the overall levels of cardiolipin, can result in mitochondrial dysfunction, which is a characteristic feature of many diseases. In this review, we outline the various functions of cardiolipin within the cells of the CNS, including neurons, astrocytes, microglia, and oligodendrocytes. In addition, we discuss the role cardiolipin may play in the pathogenesis of the neurodegenerative disorders Alzheimer’s disease and Parkinson’s disease, as well as traumatic brain injury.     

Expression Profile Analysis of Neurodegenerative Disease: Advances in Specificity and Resolution

Microarray technology has become a common tool for developing expression profiles. Initially used in the analysis of cells lines and homogeneous tissues, this platform has been applied to more diverse tissues, such as the brain. Several neural disorders have already been profiled by microarrays using relatively large amounts of tissue. This data has unveiled many genes with differential expression between normal and diseased tissue that could potentially be used as gene markers for these afflictions. Because of the heterogeneity of the CNS, it is likely that small differences between gene expression in these studies would be enhanced by the sampling of a subset of cells based on these newly characterized gene markers. Subtraction of normal, unaffected cells from the sample may also result in a more accurate profile of a diseased cell. Expression profile studies from several neuropathological states are presented, with emphasis placed on those studies using small samples of cellular material and those using specialized methods of cell isolation and RNA amplification.     

The mystery and magic of glia: a perspective on their roles in health and disease

In this perspective, I review recent evidence that glial cells are critical participants in every major aspect of brain development, function, and disease. Far more active than once thought, glial cells powerfully control synapse formation, function, and blood flow. They secrete many substances whose roles are not understood, and they are central players in CNS injury and disease. I argue that until the roles of nonneuronal cells are more fully understood and considered, neurobiology as a whole will progress only slowly.     

IGF-I mediated survival pathways in normal and malignant cells

The type-I and -II insulin-like growth factors (IGF-I, II) are now established as survival- or proliferation-factors in many in vitro systems. Of note IGFs provide trophic support for multiple cell types or organ cultures explanted from various species, and delay the onset of programmed cell death (apoptosis) through the mitochondrial (intrinsic pathway) or by antagonizing activation of cytotoxic cytokine signaling (extrinsic pathway). In some instances, IGFs protect against other forms of death such as necrosis or autophagy. The effect of IGFs on cell survival appears to be context specific, being determined both by the cell origin (tissue specific) and the cellular stress that induces loss of cellular viability. In many human cancers, there is a strong association with dysregulated IGF signaling, and this association has been extensively reviewed recently. IGF-regulation is also disrupted in childhood cancers as a consequence of chromosomal translocations. IGFs are implicated also in acute renal failure, traumatic injury to brain tissue, and cardiac disease. This article focuses on the role of IGFs and their cellular signaling pathways that provide survival signals in stressed cells.     

Regeneration of the adult zebrafish brain from neurogenic radial glia-type progenitors

Severe traumatic injury to the adult mammalian CNS leads to life-long loss of function. By contrast, several non-mammalian vertebrate species, including adult zebrafish, have a remarkable ability to regenerate injured organs, including the CNS. However, the cellular and molecular mechanisms that enable or prevent CNS regeneration are largely unknown. To study brain regeneration mechanisms in adult zebrafish, we developed a traumatic lesion assay, analyzed cellular reactions to injury and show that adult zebrafish can efficiently regenerate brain lesions and lack permanent glial scarring. Using Cre-loxP-based genetic lineage-tracing, we demonstrate that her4.1-positive ventricular radial glia progenitor cells react to injury, proliferate and generate neuroblasts that migrate to the lesion site. The newly generated neurons survive for more than 3 months, are decorated with synaptic contacts and express mature neuronal markers. Thus, regeneration after traumatic lesion of the adult zebrafish brain occurs efficiently from radial glia-type stem/progenitor cells.     

Matrix metalloproteinase‐3 in the central nervous system: a look on the bright side

Matrix metalloproteinases (MMPs) are a large family of proteases involved in many cell‐matrix and cell‐cell signalling processes through activation, inactivation or release of extracellular matrix (ECM) and non‐ECM molecules, such as growth factors and receptors. Uncontrolled MMP activities underlie the pathophysiology of many disorders. Also matrix metalloproteinase‐3 (MMP‐3) or stromelysin‐1 contributes to several pathologies, such as cancer, asthma and rheumatoid arthritis, and has also been associated with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and multiple sclerosis. However, based on defined MMP spatiotemporal expression patterns, the identification of novel candidate molecular targets and in vitro and in vivo studies, a beneficial role for MMPs in CNS physiology and recovery is emerging. The main purpose of this review is to shed light on the recently identified roles of MMP‐3 in normal brain development and in plasticity and regeneration after CNS injury and disease. As such, MMP‐3 is correlated with neuronal migration and neurite outgrowth and guidance in the developing CNS and contributes to synaptic plasticity and learning in the adult CNS. Moreover, a strict spatiotemporal MMP‐3 up‐regulation in the injured or diseased CNS might support remyelination and neuroprotection, as well as genesis and migration of stem cells in the damaged brain.     

3-D Imaging and Analysis of Neurons Infected In Vivo with Toxoplasma gondii

Toxoplasma gondii is an obligate, intracellular parasite with a broad host range, including humans and rodents. In both humans and rodents, Toxoplasma establishes a lifelong persistent infection in the brain. While this brain infection is asymptomatic in most immunocompetent people, in the developing fetus or immunocompromised individuals such as acquired immune deficiency syndrome (AIDS) patients, this predilection for and persistence in the brain can lead to devastating neurologic disease. Thus, it is clear that the brain-Toxoplasma interaction is critical to the symptomatic disease produced by Toxoplasma, yet we have little understanding of the cellular or molecular interaction between cells of the central nervous system (CNS) and the parasite. In the mouse model of CNS toxoplasmosis it has been known for over 30 years that neurons are the cells in which the parasite persists, but little information is available about which part of the neuron is generally infected (soma, dendrite, axon) and if this cellular relationship changes between strains. In part, this lack is secondary to the difficulty of imaging and visualizing whole infected neurons from an animal. Such images would typically require serial sectioning and stitching of tissue imaged by electron microscopy or confocal microscopy after immunostaining. By combining several techniques, the method described here enables the use of thick sections (160 µm) to identify and image whole cells that contain cysts, allowing three-dimensional visualization and analysis of individual, chronically infected neurons without the need for immunostaining, electron microscopy, or serial sectioning and stitching. Using this technique, we can begin to understand the cellular relationship between the parasite and the infected neuron.     

对比不同类型干细胞对于缺血性脑卒中治疗的研究进展

成人中枢神经系统存在着一定量的神经干细胞,其具有两大关键能力;自我更新和多向分化潜能。缺血性脑卒中是一种由于由脑血流的缺失或减少引起的脑动脉闭塞,进而导致脑组织梗死的脑血管疾病。虽然对于脑损伤的药物治疗已经取得了一定的成果,但目前以干细胞为基础的治疗方法仍成为了研究热点。无论是内源性神经干细胞还是外源性神经干细胞移植均可在脑损伤后向远端损伤区迁移并分化成新的神经细胞,从而在中枢神经系统疾病尤其是脑梗死后进行组织修复和功能恢复。因此在这篇综述中,我们主要探讨不同类型的干细胞对脑梗死介导的脑损伤的应用潜能,对比不同类型干细胞对缺血性脑卒中的治疗优缺点。     

Cell-specific and concentration-dependent actions of interleukin-1 in acute brain inflammation

Interleukin (IL)-1 is a pivotal pro-inflammatory cytokine and an important mediator of both acute and chronic central nervous system (CNS) injuries. Despite intense research in CNS IL-1 biology over the past two decades, its precise mechanism of action in inflammatory responses to acute brain disorders remains largely unknown. In particular, much effort has been focussed on using in vitro approaches to better understand the cellular and signalling mechanisms of actions of IL-1, yet some discrepancies in the literature regarding the effects produced by IL-1β in in vitro paradigms of injury still exist, particularly as to whether IL-1 exerts neurotoxic or neuroprotective effects. Here we aim to review the cell-specific and concentration-dependent actions of IL-1 in brain cells, to depict the mechanism by which this cytokine induces neurotoxicity or neuroprotection in acute brain injury.     

The life, death, and replacement of oligodendrocytes in the adult CNS

Oligodendrocytes (OLs) are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal signaling. The embryonic lineage and postnatal development of OLs have been well-studied and many features of the process have been described, including the origin, migration, proliferation, and differentiation of precursor cells. Less clear is the extent to which OLs and damaged/dysfunctional myelin are replaced following injury to the adult CNS. OLs and their precursors are very vulnerable to conditions common to CNS injury and disease sites, such as inflammation, oxidative stress, and elevated glutamate levels leading to excitotoxicity. Thus, these cells become dysfunctional or die in multiple pathologies, including Alzheimer's disease, spinal cord injury, Parkinson's disease, ischemia, and hypoxia. However, studies of certain conditions to date have detected spontaneous OL replacement. This review will summarize current information on adult OL progenitors, mechanisms that contribute to OL death, the consequences of their loss and the pathological conditions in which spontaneous oligodendrogenesis from endogenous precursors has been observed in the adult CNS.