Proper development and function of the mammalian central nervous system (CNS) depend critically on the activity of parenchymal sentinels referred to as microglia. Although microglia were first described as ramified brain-resident phagocytes, research conducted over the past century has expanded considerably upon this narrow view and ascribed many functions to these dynamic CNS inhabitants. Microglia are now considered among the most versatile cells in the body, possessing the capacity to morphologically and functionally adapt to their ever-changing surroundings. Even in a resting state, the processes of microglia are highly dynamic and perpetually scan the CNS. Microglia are in fact vital participants in CNS homeostasis, and dysregulation of these sentinels can give rise to neurological disease. In this review, we discuss the exciting developments in our understanding of microglial biology, from their developmental origin to their participation in CNS homeostasis and pathophysiological states such as neuropsychiatric disorders, neurodegeneration, sterile injury responses, and infectious diseases. We also delve into the world of microglial dynamics recently uncovered using real-time imaging techniques.

Devic’s disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty‐two lesions were examined from nine autopsy cases of clinically confirmed Devic’s disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3⁺ and CD8⁺ T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.

Traumatic brain injury (TBI) is a diverse group of brain injuries that vary in cause, severity, pathogenesis, and clinical outcome. As public awareness of TBI and its consequences increases, there is a growing need to understand the underlying mechanisms and develop therapeutic interventions. Within the United States alone, nearly 2 million people sustain a TBI annually, contributing to one-third of all injury-related deaths. Individuals from all nations and demographics are affected, including athletes, military troops, and individuals with unintentional injuries.^1-3 Traumatic brain injury is a significant cause of mortality in children and young adults, and the incidence in older individuals has increased with the average life span.⁴ Mild TBI (mTBI) is the most frequent type diagnosed, typically resulting in post-TBI survival. Traumatic brain injury is suspected to contribute to a variety of chronic degenerative processes, including chronic traumatic encephalopathy, Alzheimer disease, and Parkinson disease.⁵ Traumatic brain injury is initiated by the application of mechanical force to the head, which can occur with or without loss of consciousness. This then triggers a series of cerebral events that depend in part on the nature and location of the injury. A major challenge associated with treating patients with TBI is the diverse pathologic and pathogenic mechanisms that become operational after injuries. For example, TBI often promotes disruption of blood-brain barrier (BBB) integrity and the neurovascular unit, which can result in vascular leakage, edema, hemorrhage, and hypoxia. Other pathologic mechanisms include cell death within the meninges and brain parenchyma, stretching and tearing of axonal fibers, and disruptions at the junctions between white and gray matter, stemming from rotational forces that cause shearing injuries.⁶ All these primary pathologic mechanisms are accompanied by cellular and molecular cascades leading to inflammation and additional cell death. This review focuses on our current understanding of the sterile immune reaction to TBI and some clinical successes in treating patients with TBI.