The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The ...CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These myeloid cells in the CNS parenchyma and at CNS-periphery interfaces are highly specialized but also extremely plastic cells that immediately react to any changes in CNS homeostasis and become reactive in the context of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease. However, when the blood-brain barrier is impaired during CNS diseases such as multiple sclerosis or altered with cerebral ischemia, peripheral adaptive and innate immune cells, including monocytes, neutrophils, T cells and B cells, can enter the CNS, where they execute distinct cell-mediated effects. On the basis of these observations, we assess strategies for targeting peripheral immune cells to reduce CNS disease burden.
Mononuclear phagocytic cells in the CNS used to be defined according to their anatomical location and surface marker expression. Recently, this concept has been challenged by the results of ...developmental and gene expression profiling studies that have used novel molecular biological tools to unravel the origin of microglia and to define their role as specialized tissue macrophages with long lifespans. Here, we describe how these results have redefined microglia and helped us to understand how different myeloid cell populations operate in the CNS based on their cell-specific gene expression signatures, distinct ontogeny and differential functions. Moreover, we describe the vulnerability of microglia to dysfunction and propose that myelomonocytic cells might be used in the treatment of neurological and psychiatric disorders that are characterized by primary or secondary 'microgliopathy'.
Microglia were first recognized as a distinct cell population in the CNS one century ago. For a long time, they were primarily considered to be phagocytes responsible for removing debris during CNS ...development and disease. More recently, advances in imaging and genetics and the advent of single-cell technologies provided new insights into the much more complex and fascinating biology of microglia. The ontogeny of microglia was identified, and their functions in health and disease were better defined. Although many questions about microglia and their roles in human diseases remain unanswered, the prospect of targeting microglia for the treatment of neurological and psychiatric disorders is tantalizing.
We’ve learned much in the past 100 years about the roles and mechanisms of microglia in CNS development and disease using animal models, but a gap still exists in translating this knowledge to humans.
Microglia are the resident macrophages of the central nervous system (CNS). They have important physiological functions in maintaining tissue homeostasis but also contribute to CNS pathology. ...Microglia respond to changes in the microenvironment, and the resulting reactive phenotype can be very diverse, with both neuroinflammatory and neuroprotective properties, illustrating the plasticity of these cells. Recent progress in understanding the autoimmune neuroinflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis suggests major roles for microglia in the disease, which have drastically changed our view on the function of microglia in MS.
Microglia are shaped by their ontogeny and the specific CNS microenvironment, defining the functional plasticity of these cells. Microglia can respond to different types of stimuli, including exogenous infectious pathogens as well as injurious self-proteins, and initiate a neuroinflammatory response.
In MS, microglia alter their transcriptional profile and become ‘disease-associated microglia’ (DAM). DAM cells in EAE display a profuse inflammatory phenotype, in contrast to other neurodegenerative diseases.
In MS and EAE, microglia induce different effector functions that can be both neuroprotective and detrimental. Currently, it is believed that the initial response of microglia is beneficial, aiming to resolve the insult, but that chronic activation of microglia contributes to neurodegeneration.
Microglia are the resident macrophages of the central nervous system (CNS), which sit in close proximity to neural structures and are intimately involved in brain homeostasis. The microglial ...population also plays fundamental roles during neuronal expansion and differentiation, as well as in the perinatal establishment of synaptic circuits. Any change in the normal brain environment results in microglial activation, which can be detrimental if not appropriately regulated. Aberrant microglial function has been linked to the development of several neurological and psychiatric diseases. However, microglia also possess potent immunoregulatory and regenerative capacities, making them attractive targets for therapeutic manipulation. Such rationale manipulations will, however, require in-depth knowledge of their origins and the molecular mechanisms underlying their homeostasis. Here, we discuss the latest advances in our understanding of the origin, differentiation, and homeostasis of microglial cells and their myelomonocytic relatives in the CNS.
Microglia are resident immune cells in the central nervous system (CNS) that are capable of carrying out prominent and various functions during development and adulthood under both homeostatic and ...disease conditions. Although microglia are traditionally thought to be heterogeneous populations, which potentially allows them to achieve a wide range of responses to environmental changes for the maintenance of CNS homeostasis, a lack of unbiased and high-throughput methods to assess microglia heterogeneity has prevented the study of spatially and temporally distributed microglia subsets. The recent emergence of novel single-cell techniques, such as cytometry by time-of-flight mass spectrometry (CyTOF) and single-cell RNA sequencing, enabled scientists to overcome such limitations and reveal the surprising context-dependent heterogeneity of microglia. In this review, we summarize the current knowledge about the spatial, temporal, and functional diversity of microglia during development, homeostasis, and disease in mice and humans.
In this review, Masuda et al. summarize the current knowledge, open questions, and future directions regarding the spatial, temporal, and functional multiplicity of microglia during development, homeostasis, and disease in both mice and humans.
Type I interferons (IFNs), IFN‐α and IFN‐β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via ...activation of numerous pattern recognition receptors, including the Toll‐like receptor signaling network, retinoic acid‐inducible gene‐1 (RIG‐1), melanoma differentiation‐associated protein‐5 (MDA‐5) and interferon gamma‐inducible protein‐16 (IFI‐16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon‐stimulated gene expression have been linked to several CNS diseases termed “interferonopathies” including Aicardi–Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)‐deficiency. In contrast, in the CNS of mice with virus‐induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well‐balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain ‘interferonopathies’.
Main Points
USP18 deficiency represents a novel genetic etiology of a type I interferonopathy.
Type I interferon homeostasis is critical for neuronal survival and cognitive function during aging.
Oversupply of type I interferons elicits “sickness behavior”.
Among the myeloid cells in the central nervous system (CNS) microglia are the main representatives of the innate immune system. Microglial fulfil tasks beyond phagocytosing debris and host defense ...against invading microorganism. During brain development microglia guide for example neurons for proper CNS formation, in adulthood they maintain tissue homeostasis and in aging microglia may become pro‐inflammatory and finally exhausted. Recently, several endogenous and exogenous factors were identified that essentially shape the microglial phenotype during both steady‐state and pathological conditions. On the one hand, microglia receive inputs from CNS‐endogenous sources for example, via crosstalk with other glial cells and neurons but on the other hand microglia are also highly modulated by external signals. Among them, host microbiota—the host's resident bacteria—are vital regulators of the CNS innate immune system. This review summarizes key extrinsic and intrinsic factors, with special focus on the host microbiota, that essentially influence microglia functions and states during development, homeostasis, and disease.
Main points
Host microbiota shape maturation and function of microglia during homeostatic conditions.
Short‐chain fatty acids restore deficits in microglia from germ‐free housed mice.
Host bacteria might influence several CNS diseases via microglia
The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the ...CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.
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