Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases.

Microglia Function in the Central Nervous System During Health and Neurodegeneration.

As the immune-competent cells of the brain, microglia play an increasingly important role in maintaining normal brain function. They invade the brain early in development, transform into a highly ramified phenotype, and constantly screen their environment. Microglia are activated by any type of pathologic event or change in brain homeostasis. This activation process is highly diverse and depends on the context and type of the stressor or pathology. Microglia can strongly influence the pathologic outcome or response to a stressor due to the release of a plethora of substances, including cytokines, chemokines, and growth factors. They are the professional phagocytes of the brain and help orchestrate the immunological response by interacting with infiltrating immune cells. We describe here the diversity of microglia phenotypes and their responses in health, aging, and disease. We also review the current literature about the impact of lifestyle on microglia responses and discuss treatment options that modulate microglial phenotypes.

Microglia in Physiology and Disease

Microglia are the only immune cells that permanently reside in the central nervous system (CNS) alongside neurons and other types of glial cells. The past decade has witnessed a revolution in our understanding of their roles during normal physiological conditions. Cutting-edge techniques revealed that these resident immune cells are critical for proper brain development, actively maintain health in the mature brain, and rapidly adapt their function to physiological or pathophysiological needs. In this review, we highlight recent studies on microglial origin (from the embryonic yolk sac) and the factors regulating their differentiation and homeostasis upon brain invasion. Elegant experiments tracking microglia in the CNS allowed studies of their unique roles compared with other types of resident macrophages. Here we review the emerging roles of microglia in brain development, plasticity and cognition, and discuss the implications of the depletion or dysfunction of microglia for our understanding of disease pathogenesis. Immune activation, inflammation and various other conditions resulting in undesirable microglial activity at different stages of life could severely impair learning, memory and other essential cognitive functions. The diversity of microglial phenotypes across the lifespan, between compartments of the CNS, and sexes, as well as their crosstalk with the body and external environment, is also emphasised. Understanding what defines particular microglial phenotypes is of major importance for future development of innovative therapies controlling their effector functions, with consequences for cognition across chronic stress, ageing, neuropsychiatric and neurological diseases.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP272134

Microglia across the lifespan: from origin to function in brain development, plasticity and cognition.

Glia are essential for brain functioning during development and in the adult brain. Here, we discuss the various roles of both microglia and astrocytes, and their interactions during brain development. Although both cells are fundamentally different in origin and function, they often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis and synaptic pruning. Due to their important instructive roles in these processes, dysfunction of microglia or astrocytes during brain development could contribute to neurodevelopmental disorders and potentially even late-onset neuropathology. A better understanding of the origin, differentiation process and developmental functions of microglia and astrocytes will help to fully appreciate their role both in the developing as well as in the adult brain, in health and disease.

/pdf/the-indispensable-roles-of-microglia-and-astrocytes-during-1rxhg6l1h7.pdf

The Indispensable Roles of Microglia and Astrocytes during Brain Development

Various lines of evidence suggest that immune system dysregulation has a key role in autism spectrum disorder (ASD). Estes and McAllister review this evidence, covering genetic and maternal immune system-related risk factors, chronic immune system changes in individuals with ASD and in animal models, and potential pathophysiological mechanisms. Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD). Several ASD risk genes encode components of the immune system and many maternal immune system-related risk factors — including autoimmunity, infection and fetal reactive antibodies — are associated with ASD. In addition, there is evidence of ongoing immune dysregulation in individuals with ASD and in animal models of this disorder. Recently, several molecular signalling pathways — including pathways downstream of cytokines, the receptor MET, major histocompatibility complex class I molecules, microglia and complement factors — have been identified that link immune activation to ASD phenotypes. Together, these findings indicate that the immune system is a point of convergence for multiple ASD-related genetic and environmental risk factors.

/pdf/immune-mediators-in-the-brain-and-peripheral-tissues-in-2kh7560g1l.pdf

Immune mediators in the brain and peripheral tissues in autism spectrum disorder

arising from N C Derecki et al , 105–109 (2012); doi:101038/nature10907
 Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the X chromosomal gene MECP2 (ref 1), and its treatment so far is symptomatic Mecp2 disruption in mice phenocopies major features of the syndrome2 that can be reversed after Mecp2 re-expression3 Recently, Derecki et al4 reported that transplantation of wild-type bone marrow into lethally irradiated Mecp2-null (Mecp2tm11Jae/y) mice prevented neurological decline and early death by restoring microglial phagocytic activity against apoptotic targets4, and clinical trials of bone marrow transplantation (BMT) for patients with Rett syndrome have thus been initiated5 We aimed to replicate and extend the BMT experiments in three different Rett syndrome mouse models, but found that despite robust microglial engraftment, BMT from wild-type donors did not prevent early death or ameliorate neurological deficits Furthermore, early and specific Mecp2 genetic expression in microglia did not rescue Mecp2-deficient mice

Wild-type microglia do not reverse pathology in mouse models of Rett syndrome

Nature 521, E1–E4 (2015); doi:10.1038/nature14444 In this Brief Communication Arising, the first name of author Sebastien Vingeau was misspelled ‘Sebastian’. In addition, the labels (‘WT→KO’ and ‘KO→WT’) of the two bottom panels in Extended Data Figure 1b were swapped. Both errors have been corrected online.

/pdf/corrigendum-wild-type-microglia-do-not-reverse-pathology-in-5l6j2uouiv.pdf

Corrigendum: Wild-type microglia do not reverse pathology in mouse models of Rett syndrome.

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Wild-type microglia do not reverse pathology in mouse models of Rett syndrome

Corrigendum: Wild-type microglia do not reverse pathology in mouse models of Rett syndrome.