Microglia: biology and pathology
TL;DR: A critical review of the literature shows that the concept of “(micro)glial inflammation” is still open to interpretation, despite a prevailing slant towards a negative meaning, and research on the role of microglia in synaptic plasticity is expected to yield an answer to the question whether microglias are the brain’s electricians.
Abstract: The past 20 years have seen a gain in knowledge on microglia biology and microglia functions in disease that exceeds the expectations formulated when the microglia “immune network” was introduced. More than 10,000 articles have been published during this time. Important new research avenues of clinical importance have opened up such as the role of microglia in pain and in brain tumors. New controversies have also emerged such as the question of whether microglia are active or reactive players in neurodegenerative disease conditions, or whether they may be victims themselves. Premature commercial interests may be responsible for some of the confusion that currently surrounds microglia in both the Alzheimer and Parkinson’s disease research fields. A critical review of the literature shows that the concept of “(micro)glial inflammation” is still open to interpretation, despite a prevailing slant towards a negative meaning. Perhaps the most exciting foreseeable development concerns research on the role of microglia in synaptic plasticity, which is expected to yield an answer to the question whether microglia are the brain’s electricians. This review provides an analysis of the latest developments in the microglia field.
Citations
More filters
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: The mechanisms of neurotoxicity associated with chronic microglia activation are reviewed and the role of neuronal death and microglial ROS driving the chronic and toxic microglian phenotype is discussed.
771 citations
TL;DR: It is shown that extracellular α-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia, suggesting that both these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.
Abstract: Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.
634 citations
TL;DR: The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment as mentioned in this paper and the median treatment duration to onset of symptoms was 25 months (range 6-80 months).
Abstract: Summary Background Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. Recent developments The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6–80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. Where next? Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.
590 citations
TL;DR: Experimental work on the complex and varied responses of microglia in terms of both detrimental and beneficial effects is reviewed.
577 citations
Cites background from "Microglia: biology and pathology"
...It is commonly believed that these cells migrate into the CNS during development, and may continue to invade over the course of life, particularly after injury or insult.(3) This review will explore the current research on microglial responses to CNS injury....
[...]
References
More filters
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: 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.
4,372 citations
"Microglia: biology and pathology" refers background in this paper
...More than a decade ago, Georg Kreutzberg coined the term ‘‘microglial sensor of pathology’’ [97] which captures the essence of microglial cell function and, not surprisingly, has become a widely accepted notion today....
[...]
TL;DR: The cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures are reviewed and the concept of macrophage activation in the context of the immune response is revisit.
Abstract: Macrophages are innate immune cells with well-established roles in the primary response to pathogens, but also in tissue homeostasis, coordination of the adaptive immune response, inflammation, resolution, and repair. These cells recognize danger signals through receptors capable of inducing specialized activation programs. The classically known macrophage activation is induced by IFN-gamma, which triggers a harsh proinflammatory response that is required to kill intracellular pathogens. Macrophages also undergo alternative activation by IL-4 and IL-13, which trigger a different phenotype that is important for the immune response to parasites. Here we review the cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures. We draw attention to discrepancies found between mouse and human models of alternative activation. The evidence for in vivo alternative activation of macrophages is also analyzed, with nematode infection as prototypic disease. Finally, we revisit the concept of macrophage activation in the context of the immune response.
2,515 citations
"Microglia: biology and pathology" refers background in this paper
...However, it should be pointed out that there are known species differences even between mice and humans concerning macrophage activation pathways [119]....
[...]
...when alternative macrophage activation pathways [119] are involved, will also be of importance for our under-...
[...]
TL;DR: Examination of the distribution of microglia in the normal adult mouse brain using immunocytochemical detection of the macrophage specific plasma membrane glycoprotein F4/80 found no evidence of monocyte-like cells in the adult CNS.
1,810 citations
"Microglia: biology and pathology" refers result in this paper
...Finally, it is worth mentioning that in contrast to a study in mice [100], the human substantia nigra does not contain the highest density of microglial cells [124]....
[...]
TL;DR: The recent recognition that astrocytes are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astroCytes.
Abstract: For decades, astrocytes have been considered to be non-excitable support cells of the brain. However, this view has changed radically during the past twenty years. The recent recognition that they are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astrocytes. Today, astrocytes are seen as local communication elements of the brain that can generate various regulatory signals and bridge structures (from neuronal to vascular) and networks that are otherwise disconnected from each other. Examples of their specific and essential roles in normal physiological processes have begun to accumulate, and the number of diseases known to involve defective astrocytes is increasing.
1,635 citations
"Microglia: biology and pathology" refers background in this paper
...through the regulated release of ‘gliotransmitters’ including glutamate [187]....
[...]