Microglia: a sensor for pathological events in the CNS
TL;DR: An understanding of intercellular signalling pathways for microglia proliferation and activation could form a rational basis for targeted intervention on glial reactions to injuries in the CNS.
About: This article is published in Trends in Neurosciences.The article was published on 1996-08-01. It has received 4372 citations till now. The article focuses on the topics: Neuroinflammation & Neuroglia.
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TL;DR: Using in vivo two-photon imaging in neocortex, it is found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions.
Abstract: Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.
4,458 citations
TL;DR: Extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglia response towards injury.
Abstract: Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.
3,251 citations
TL;DR: This review focuses on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.
Abstract: Microglial cells constitute the resident macrophage population of the CNS. Recent in vivo studies have shown that microglia carry out active tissue scanning, which challenges the traditional notion of 'resting' microglia in the normal brain. Transformation of microglia to reactive states in response to pathology has been known for decades as microglial activation, but seems to be more diverse and dynamic than ever anticipated—in both transcriptional and nontranscriptional features and functional consequences. This may help to explain why engagement of microglia can be either neuroprotective or neurotoxic, resulting in containment or aggravation of disease progression. Moreover, little is known about the heterogeneity of microglial responses in different pathologic contexts that results from regional adaptations or from the progression of a disease. In this review, we focus on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.
3,238 citations
TL;DR: Current studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains, and microglial cells are considered the most susceptible sensors of brain pathology.
Abstract: Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.
2,998 citations
TL;DR: It is shown that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and themicroglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3.
2,864 citations
Cites background from "Microglia: a sensor for pathologica..."
...…are the resident CNS immune cells which have long been recognized as rapid responders to injury and disease, play- ing a role in a broad range of processes such as tissue inflammation and clearance of cellular debris (Hanisch and Kettenmann, 2007; Kreutzberg, 1996; Ransohoff and Perry, 2009)....
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...Microglia are the resident CNS immune cells which have long been recognized as rapid responders to injury and disease, playing a role in a broad range of processes such as tissue inflammation and clearance of cellular debris (Hanisch and Kettenmann, 2007; Kreutzberg, 1996; Ransohoff and Perry, 2009)....
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References
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TL;DR: In this article, a synergistic effect between A beta and interferon-gamma was found to trigger the production of reactive nitrogen intermediates and tumour-necrosis factor-alpha (TNF-alpha) from microglia.
Abstract: Alzheimer's disease is the most common cause of progressive intellectual failure. The lesions that develop, called senile plaques, are extracellular deposits principally composed of insoluble aggregates of beta-amyloid protein (A beta), infiltrated by reactive microglia and astrocytes. Although A beta, and a portion of it, the fragment 25-35 (A beta (25-35)), have been shown to exert a direct toxic effect on neurons, the role of microglia in such neuronal injury remains unclear. Here we report a synergistic effect between A beta and interferon-gamma (IFN-gamma) in triggering the production of reactive nitrogen intermediates and tumour-necrosis factor-alpha (TNF-alpha) from microglia. Furthermore, using co-culture experiments, we show that activation of microglia with IFN-gamma and A beta leads to neuronal cell injury in vitro. These findings suggest that A beta and IFN-gamma activate microglia to produce reactive nitrogen intermediates and TNF-alpha, and this may have a role in the pathogenesis of neuronal degeneration observed in ageing and Alzheimer's disease.
1,337 citations
TL;DR: Activated microglia rather than astrocytes or endothelial cells are the candidates as intrinsic antigen presenting cel of the brain due to their pronounced antigen presenting function in vitro.
1,122 citations
TL;DR: Interference with the microglial activation or the productions of cytotoxic metabolites by microglia may offer new therapeutic opportunities for the prevention of neuronal cell death in CNS disease.
Abstract: The most characteristic property of microglia is their swift activation in response to neuronal stress and their capacity for site-directed phagocytosis. The transformation of microglia into intrinsic brain macrophages appears to be under strict control and takes place if neuronal and/or terminal degeneration occurs in response to nerve lesion. The differentiation of microglia into brain macrophages is accompanied by the release of several secretory products, e.g., proteinases, cytokines, reactive oxygen intermediates, and reactive nitrogen intermediates. Interference with the microglial activation or the productions of cytotoxic metabolites by microglia may thus offer new therapeutic opportunities for the prevention of neuronal cell death in CNS disease.
1,032 citations
TL;DR: A role of CNS microglia as a source of defense cells in the CNS capable of carrying out certain immune functions autonomously is supported, which may lead to a redefinition of the often cited “immune privilege” of the brain.
Abstract: The present review summarizes recently acquired data in vivo, which support a role of CNS microglia as a source of defense cells in the CNS capable of carrying out certain immune functions autonomously. We have kept the following discussion restricted to microglial cells and have not included work on the immunological functions of astrocytes, which has been recently reviewed elsewhere (Fontana et al.: Immunological Reviews 137:3521-3527, 1987). Resting microglia are scattered uniformly throughout the CNS forming a network of potential immunoeffector cells, which can be activated by stimuli ranging from peripheral nerve injury over viral infections to direct mechanical brain trauma. The term "activated microglia" is used here to describe proliferating cells that demonstrate changes in their immunophenotype but have not undergone transformation into brain macrophages. Such a transformation can be stimulated by neuronal death but not by sublethal neuronal injury. Microglia may function as antigen-presenting cells and may thus represent the effector cell responsible for the recruitment of lymphocytes to the brain resulting in an inflammatory reaction. The recent developments in the understanding of microglial cell function may lead to a redefinition of the often cited "immune privilege" of the brain.
941 citations
TL;DR: Findings suggest that interleukin-1, released by inflammatory cells, may promote the formation of scars by astroglia in the damaged mammalian brain.
Abstract: The interleukins, which have a regulatory role in immune function, may also mediate inflammation associated with injury to the brain. In experiments to determine the effect of these peptide hormones on glial cell proliferation in culture, interleukin-1 was a potent mitogen for astroglia but had no effect on oligodendroglia. Interleukin-2 did not alter the growth of either type of glial cell. Activity similar to that of interleukin-1 was detected in brains of adult rats 10 days after the brains had been injured. These findings suggest that interleukin-1, released by inflammatory cells, may promote the formation of scars by astroglia in the damaged mammalian brain.
841 citations