Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed ...societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.
Microglial research has entered a fertile, dynamic phase characterized by novel technologies including two-photon imaging, whole-genome transcriptomic and epigenomic analysis with complementary ...bioinformatics, unbiased proteomics, cytometry by time of flight (CyTOF; Fluidigm) cytometry, and complex high-content experimental models including slice culture and zebrafish. Against this vivid background of newly emerging data, investigators will encounter in the microglial research literature a body of published work using the terminology of macrophage polarization, most commonly into the M1 and M2 phenotypes. It is the assertion of this opinion piece that microglial polarization has not been established by research findings. Rather, the adoption of this schema was undertaken in an attempt to simplify data interpretation at a time when the ontogeny and functional significance of microglia had not yet been characterized. Now, terminology suggesting established meaningful pathways of microglial polarization hinders rather than aids research progress and should be discarded.
Microglia originate from erythromyeloid progenitors (EMPs) in the yolk sac and develop in the forming CNS. Microglia are fundamental for the development and function of a healthy brain. By contrast, ...their role in immune host defense of the CNS remains speculative, given the immune privilege of this organ. Alterations in microglia functionality are involved in brain aging, as well as in neurodegenerative disease severity and progression. The combination of their ontogeny with the influence of the complex environment of the CNS makes microglia a unique cell population. Recent observations about microglia ontogeny combined with extensive gene expression profiling allow us to better capture the variety of nuances that microglia can manifest. Here, we provide a contemporary appraisal of microglial uniqueness based on their origin, functions, and expression profiles. Furthermore, we give an overview of the impact of aging and neurodegenerative diseases on microglia transcriptomes.
Cell identity integrates the combination of ontogeny and the dynamic influence of the tissue environment. Crotti and Ransohoff update our understanding of microglia based on their origin, functions, and expression profiles, resulting from the influence of the CNS.
Based on discoveries enabled by new technologies and analysis using novel computational tools, neuroscience can be re-conceived in terms of information exchange in dense networks of intercellular ...connections rather than in the context of individual populations, such as glia or neurons. Cross-talk between neurons and microglia or astrocytes has been addressed, however, the manner in which non-neuronal cells communicate and interact remains less well-understood. We review this intriguing crosstalk among CNS cells, focusing on astrocytes and microglia and how it contributes to brain development and neurodegenerative diseases. The goal of studying these intercellular communications is to promote our ability to combat incurable neurological disorders.
The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, ...namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.
The central nervous system (CNS) comprises the brain, spinal cord, optic nerves and retina, and contains post-mitotic, delicate cells. As the rigid coverings of the CNS render swelling dangerous and ...destructive, inflammatory reactions must be carefully controlled in CNS tissues. Nevertheless, effector immune responses that protect the host during CNS infection still occur in the CNS. Here, we describe the anatomical and cellular basis of immune surveillance in the CNS, and explain how this shapes the unique immunology of these tissues. The Review focuses principally on insights gained from the study of autoimmune responses in the CNS and to a lesser extent on models of infectious disease. Furthermore, we propose a new model to explain how antigen-specific T cell responses occur in the CNS.
Highlights • The inflammatory reaction after TBI follows a stereotyped time course. • Multiple cellular and molecular mediators may contribute to secondary injury. • Chemokines mediate peripheral ...immune cell recruitment after TBI. • Chemokine pathways are altered after TBI and may represent therapeutic targets.
Multiple sclerosis (MS) is a spontaneous, acquired, inflammatory demyelinating disease of the human CNS. Because it involves a complex interaction between two of the most intricate biological ...systems, immune system and CNS, animal modeling has been critical for addressing MS pathogenesis. MS models were originally developed serendipitously more than 75 years ago. Immune-mediated, toxic, viral and genetic models of demyelination are now used to understand the manifold aspects of MS. MS treatments evolved in part from animal model research, and further progress is envisaged in large part because these systems have been continually refined and their use focused on questions whose relevance was established by studying the human disease.
The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed ...to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system - unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides - the concept of neuroinflammation in AD may need refinement.
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