The role of microglia in spinal cord injury (SCI) remains poorly understood and is often confused with the response of macrophages. Here, we use specific transgenic mouse lines and depleting agents ...to understand the response of microglia after SCI. We find that microglia are highly dynamic and proliferate extensively during the first two weeks, accumulating around the lesion. There, activated microglia position themselves at the interface between infiltrating leukocytes and astrocytes, which proliferate and form a scar in response to microglia-derived factors, such as IGF-1. Depletion of microglia after SCI causes disruption of glial scar formation, enhances parenchymal immune infiltrates, reduces neuronal and oligodendrocyte survival, and impairs locomotor recovery. Conversely, increased microglial proliferation, induced by local M-CSF delivery, reduces lesion size and enhances functional recovery. Altogether, our results identify microglia as a key cellular component of the scar that develops after SCI to protect neural tissue.
Inflammatory mechanisms in neurodegeneration Nichols, Michael R.; St‐Pierre, Marie‐Kim; Wendeln, Ann‐Christin ...
Journal of neurochemistry,
June 2019, Letnik:
149, Številka:
5
Journal Article
Recenzirano
Odprti dostop
This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD). Theories have been postulated, tested, and modified over several decades. The ...findings have further bolstered the belief that microglia‐mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.
This review will discuss the nexus between microglia, neuroinflammation, and Alzheimer's disease (AD). Areas of emphasis in the article are distinct microglia phenotypes and their function, microglial recognition and response to amyloid‐β (Aβ) aggregates in AD, and the overall contributory role of microglia in AD. The cumulative data point to a dynamic interrelationship between microglial phenotype and function, as well as Aβ accumulation.
Summary
Objectives
To evaluate the impact of bariatric surgery on the pharmacokinetic (PK) parameters of orally administered medications and supplements.
Methods
Systematic searches of bibliographic ...databases were conducted to identify studies. Pooled effect estimates from different surgical procedures were calculated using a random‐effects model.
Results
Quantitative data were synthesized from 58 studies including a total of 1985 participants. Whilst 40 medications and 6 supplements were evaluated across these studies, heterogeneity and missing information reduced the scope of the meta‐analysis to the following medications and supplements: atorvastatin, paracetamol, omeprazole, midazolam, vitamin D, calcium, zinc, and iron supplements. There were no significant differences in PK parameters post‐surgery for the drugs atorvastatin and omeprazole, and supplements calcium, ferritin, and zinc supplements. Paracetamol showed reduced clearance (mean difference MD = −15.56 L/hr, p = 0.0002, I2 = 67%), increased maximal concentration (MD = 6.90 μg/ml, p = 0.006, I2 = 92%) and increased terminal elimination half‐life (MD = 0.49 hr, p < 0.0001, I2 = 3%) post‐surgery. The remaining 36 medications and 2 supplements were included in a systematic review. Overall, 18 of the 53 drugs and supplements showed post‐operative changes in PK parameters.
Conclusion
This study demonstrates heterogeneity in practice and could not reach conclusive findings for most PK parameters. Prospective studies are needed to inform best practice and enhance patient healthcare and safety following bariatric surgery.
Microglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute to adaptive ...response of the brain and behavior toward stress using a mild and adaptive stress model – chronic restraint stress (CRS) – with wild type (WT) and CX3CR1‐GFP (CX3CR1G) mice and human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety and depressive‐like behaviors, but instead strengthened social dominance and short‐term spatial learning in WT mice. Compared to WT and CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate in social interaction before and after CRS. Microglia in WT mice underwent a series of region‐specific changes involving their phagocytosis of presynaptic vesicular glutamate transporter 2 protein, contacts with synaptic elements, CD206+microglial proportion, and gene expressions such as Cx3cr1. By contrast, CX3CR1‐deficient microglia showed decreased CD206+ while increased MHCII+ subpopulations and hypo‐ramification in the hippocampus, as well as sensitized polarization and morphological change in response to CRS. Furthermore, CD206+ microglial abundancy was positively correlated with social dominancy and microglial ramification in CX3CR1‐GFP mice. Moreover, CX3CR1 mRNA level was reduced in CRS‐treated mouse brains and showed a smaller interactome with other brain genes in the dorsal‐lateral prefrontal cortices of patients with schizophrenia. Our findings overall highlight microglia and its receptor CX3CR1 as key contributors in regulation of social behavioral adaptation to chronic stress.
MAIN POINTS
CRS primes C57BL6J mice in learning and social hierarchy.
CRS modulates microglial presynaptic pruning, especially in CD206+ microglia.
CX3CR1 regulates social submissiveness in mice and is associated with schizophrenia in humans.
Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease ...conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.
Bertrand Joseph and colleagues discuss the complexities and heterogeneity of the resident macrophage cells that play key roles in CNS immune responses, suggesting function‐based categorizations and ways for further studies.
Microglia and Neonatal Brain Injury Mallard, Carina; Tremblay, Marie-Eve; Vexler, Zinaida S.
Neuroscience,
05/2019, Letnik:
405
Journal Article
Recenzirano
Odprti dostop
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•Microglial cells guide blood–brain barrier development in embryonic brain.•Microglial cells modulate postnatal brain development and brain circuit connectivity.•Microglial cells ...mediate distinct responses in the infectious and sterile inflammatory settings.•Microglial cells protect neurovascular integrity in acute perinatal focal arterial stroke.•Microglial cells are sexually dimorphic in healthy and in diseased immature brain.
Microglial cells are now recognized as the “gate-keepers” of healthy brain microenvironment with their disrupted functions adversely affecting neurovascular integrity, neuronal homeostasis, and network connectivity. The perception that these cells are purely toxic under neurodegenerative conditions has been challenged by a continuously increasing understanding of their complexity, the existence of a broad array of microglial phenotypes, and their ability to rapidly change in a context-dependent manner to attenuate or exacerbate injuries of different nature. Recent studies have demonstrated that microglial cells exert crucial physiological functions during embryonic and postnatal brain development, some of these functions being unique to particular stages of development, and extending far beyond sensing dangerous signals and serving as antigen presenting cells. In this focused review we cover the roles of microglial cells in regulating embryonic vasculogenesis, neurogenesis, and establishing network connectivity during postnatal brain development. We further discuss context-dependent microglial contribution to neonatal brain injuries associated with prenatal and postnatal infection and inflammation, in relation to neurodevelopmental disorders, as well as perinatal hypoxia–ischemia and arterial focal stroke. We also emphasize microglial phenotypic diversity, notably at the ultrastructural level, and their sex-dependent influence on the pathophysiology of neurodevelopmental disorders.
An emerging picture suggests that glial cells' loss of beneficial roles or gain of toxic functions can contribute to neurodegenerative conditions. Among glial cells, microglia and astrocytes have ...been shown to play phagocytic roles by engulfing synapses, apoptotic cells, cell debris, and released toxic proteins. As pathogenic protein accumulation is a key feature in Parkinson's disease (PD), compromised phagocytic clearance might participate in PD pathogenesis. In contrast, enhanced, uncontrolled and potentially toxic glial clearance capacity could contribute to synaptic degeneration. Here, we summarize the current knowledge of the molecular mechanisms underlying microglial and astrocytic phagocytosis, focusing on the possible implication of phagocytic dysfunction in neuronal degeneration. Several endo-lysosomal proteins displaying genetic variants in PD are highly expressed by microglia and astrocytes. We also present the evidence that lysosomal defects can affect phagocytic clearance and discuss the therapeutic relevance of restoring or enhancing lysosomal function in PD.
Autophagy is a degradative program that maintains cellular homeostasis. Autophagy defects have been described in numerous diseases. However, analysis of autophagy rates can be challenging, ...particularly in rare cell populations or in vivo, due to limitations in currently available tools for measuring autophagy induction. Here, we describe a method to monitor autophagy by measuring phosphorylation of the protein ATG16L1. We developed and characterized a monoclonal antibody that can detect phospho-ATG16L1 endogenously in mammalian cells. Importantly, phospho-ATG16L1 is only present on newly forming autophagosomes. Therefore, its levels are not affected by prolonged stress or late-stage autophagy blocks, which can confound autophagy analysis. Moreover, we show that ATG16L1 phosphorylation is a conserved signaling pathway activated by numerous autophagy-inducing stressors. The described antibody is suitable for western blot, immunofluorescence and immunohistochemistry, and measured phospho-ATG16L1 levels directly correspond to autophagy rates. Taken together, this phospho-antibody represents an exciting tool to study autophagy induction.
Microglia have recently been implicated as key regulators of activity‐dependent plasticity, where they contribute to the removal of inappropriate or excess synapses. However, the molecular mechanisms ...that mediate this microglial function are still not well understood. Although multiple studies have implicated fractalkine signaling as a mediator of microglia–neuron communications during synaptic plasticity, it is unclear whether this is a universal signaling mechanism or whether its role is limited to specific brain regions and stages of the lifespan. Here, we examined whether fractalkine signaling mediates microglial contributions to activity‐dependent plasticity in the developing and adolescent visual system. Using genetic ablation of fractalkine's cognate receptor, CX3CR1, and both ex vivo characterization and in vivo imaging in mice, we examined whether fractalkine signaling is required for microglial dynamics and modulation of synapses, as well as activity‐dependent plasticity in the visual system. We did not find a role for fractalkine signaling in mediating microglial properties during visual plasticity. Ablation of CX3CR1 had no effect on microglial density, distribution, morphology, or motility, in either adolescent or young adult mice across brain regions that include the visual cortex. Ablation of CX3CR1 also had no effect on baseline synaptic turnover or contact dynamics between microglia and neurons. Finally, we found that fractalkine signaling is not required for either early or late forms of activity‐dependent visual system plasticity. These findings suggest that fractalkine is not a universal regulator of synaptic plasticity, but rather has heterogeneous roles in specific brain regions and life stages.
Main Points
Fractalkine signaling is not necessary for microglial roles in synaptic plasticity in the visual system during both early and late development.
Fractalkine signaling is not a universal regulator of synaptic plasticity.
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.
Microglial phenotypes: intrinsic properties and physiological roles across the lifespan. Microglia arise mainly from yolk sac primitive macrophages, reside in the brain throughout life, and maintain their numbers through a process of self‐renewal. During development (left panels), growing coverage of the CNS by immature amoeboid macrophages occurs as a result of the rapid proliferation of their population. Maturing microglia increase their number of processes and develop ramified morphologies. They are crucial for the survival of newborn neurons and progenitors, the clearance of apoptotic cells, the formation of dendritic spines, and the pruning of less active synapses. In adulthood (middle panels), ramified microglia are important effectors of plasticity, contributing to neuronal circuit maintenance and remodelling. Over the course of ageing (right panels), microglial phenotypes diversify. Hyperactivated, primed, senescent, and dark microglia are abundant in the aged brain. These phenotypes may play a significant role in synaptic loss and cognitive decline through targeted synaptic stripping or mistargeted phagocytosis.
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