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.

Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function 1, 2 . At present no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain novel insights into TBI pathogenesis, we developed a novel closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic receptor dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We additionally show that the skull bone is permeable to small molecular weight compounds and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results provide novel insights into the acute cellular response to TBI and a means to locally deliver therapeutic compounds to the site of injury.TBI encompasses injuries that range from mild to severe 1, 3 and occurs when the brain is exposed to external forces that induce focal and / or diffuse pathologies, including vascular damage, edema, axonal shearing, and neuronal cell death [4][5][6] . TBI is usually divided into two phases: the primary insult and ensuing secondary reaction. It is postulated that primary cell death cannot be prevented without avoiding the injury itself, but that secondary damage is amenable therapeutic intervention because it is driven by pathogenic parameters such as ROS 7,8 , calcium release 9 , glutamate toxicity 10, 11 , mitochondrial dysfunction 12 , inflammation 6 , etc. To date, animal models of TBI have been developed that reflect mild, Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. In humans, primary injury to the meninges and vasculature can be observed in the absence of conspicuous brain damage following minor head trauma. As part of an ongoing study of mild TBI, we evaluated research MRI with contrast from patients presenting to the emergency room within 48 hours of minor head injury. Over a period of 30 months, 142 patients were enrolled with a baseline Glasgow Coma Scale (GCS) of 15, reporting loss-ofconsciousness or post-traumatic amnesia, and a clinical computed tomography (CT) scan without evidence of injury to the parenchyma. Meningeal hemorrhag...

PD-L1 decreases anti-viral CD8+ T cell motility and PD-1 blockade restores motility in the presence of high viral loads.