Microglial cell origin and phenotypes in health and disease

Key Points In the central nervous system, microglia have important roles in maintaining tissue homeostasis and responding to infection and injury. Microglia in the brain parenchyma originate from primitive macrophages in the yolk sac and form a population that is distinct from bone marrow-derived macrophages. Microglia can exhibit distinct phenotypes depending on context. These include a quiescent phenotype under normal conditions, a 'classically activated' phenotype in the setting of infection and injury, and an 'alternatively activated' phenotype that is associated with brain tumours. A mild form of a classically activated microglial cell phenotype is frequently observed in the context of chronic neurodegenerative diseases and may be associated with the production of neurotoxic mediators. Alternatively activated microglia are associated with gliomas and are characterized by an immunosuppressive phenotype and the production of mediators that support tumour invasion. Mechanisms that maintain a quiescent phenotype under normal conditions and promote the resolution of classical activation states are regulated by cell–cell communication with neurons and other glial cells, by anti-inflammatory cytokines and by endogenous hormones that are generated locally within the CNS and act by regulating nuclear hormone receptors. Microglia are brain-resident macrophages with a distinct origin. This Review discusses the development and function of these cells, and describes the association between the different microglial cell phenotypes and disease. Microglia — resident myeloid-lineage cells in the brain and the spinal cord parenchyma — function in the maintenance of normal tissue homeostasis. Microglia also act as sentinels of infection and injury, and participate in both innate and adaptive immune responses in the central nervous system. Microglia can become activated and/or dysregulated in the context of neurodegenerative disease and cancer, and thereby contribute to disease severity. Here, we discuss recent studies that provide new insights into the origin and phenotypes of microglia in health and disease.