Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology

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). 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 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. a physiological barrier between the blood and the CNS parenchyma. The BBB is formed by endothelial cells that are joined by complex tight junctions and coated by a basement membrane and an additional membrane of astrocytic end-feet, known as the glia limitans. a tool to study local demyelination of the corpus callosum, which is induced by the administration of the copper chelator cuprizone [bis(cyclohexanone)oxaldihydrazone] via the diet (0.2% in chow) of mice during 5 weeks. Cuprizone induces oligodendrocyte cell death and concomitant activation of astrocytes and microglia. cytokines are secreted signaling molecules with pro- or anti-inflammatory functions that coordinate the cellular activity and immune responses of cells. Chemokines are a subset of cytokines that are mainly implicated in cell migration by the induction of a chemotactic gradient. Most cytokines are expressed at low levels in homeostatic conditions, but are rapidly upregulated in pathological conditions. specialized antigen-presenting cells (APCs) that are part of the innate immune system and act as a bridge to the adaptive immune system. Overall, two subsets can be discerned, classical DCs (cDCs) and plasmacytoid DCs (pDCs). Whereas cDCs mainly function as APCs in secondary lymphoid organs, pDCs react to viral infections by producing type I interferons, but are relatively poor at presenting antigens. a population of T cells that specifically recognize myelin antigens such as myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin basic protein (MBP). After activation, these cells can enter the CNS, causing cytotoxicity. the main rodent model of MS. Encephalomyelitis is a general term to describe inflammation in the brain or spinal cord. Autoimmune encephalomyelitis is caused by an abnormal immune response to a self-antigen. EAE is actively induced by peripheral immunization with myelin-specific proteins or peptides in combination with an adjuvant, or passively by transfer of encephalitogenic T cells. mononuclear phagocytes that reside in most organs of the body and that are crucially involved in the innate immune response. Macrophages are not only involved in the phagocytosis and clearance of pathogens, dead cells, and foreign particles but also contribute to tissue development and homeostasis. these are responsible for antigen presentation that is necessary for the induction of an adaptive immune response. MHC molecules bind specific epitopes and present the antigen to the immune cells. MHC-I molecules are recognized by CD8 T cells and MHC-II molecules are recognized by CD4 T cells. a sensor that detects pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), resulting in the activation of caspase 1 and the subsequent activation and secretion of IL-1β and IL-18, key innate immune cytokines. the unique transcriptome signature of adult microglia in homeostatic conditions that enables them to sense changes in the CNS environment, including endogenous ligands and microbes. Defining the microglial sensome made it possible to compare and identify changes in microglia associated with aging and pathology. The sensome comprises 100 transcripts that are highly enriched in microglia, such as P2ry12, Tmem119, Gpr34, and Csfr1.