Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.956
Filtrar
1.
Nat Neurosci ; 23(3): 337-350, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32112058

RESUMO

Tissue repair after spinal cord injury requires the mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core, which is surrounded by an astrocytic border. Here we elucidate a temporally distinct gene signature in injury-activated microglia and macrophages (IAMs) that engages axon guidance pathways. Plexin-B2 is upregulated in IAMs and is required for motor sensory recovery after spinal cord injury. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAMs away from colliding cells and facilitates matrix compaction. Our data therefore establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAMs with the injury microenvironment during wound healing.


Assuntos
Macrófagos/fisiologia , Microglia/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Traumatismos da Medula Espinal/patologia , Cicatrização/fisiologia , Animais , Axônios/fisiologia , Microambiente Celular , Locomoção/fisiologia , Camundongos , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Vias Neurais/fisiologia , Fagocitose , Recuperação de Função Fisiológica , Sensação/fisiologia , Traumatismos da Medula Espinal/metabolismo
2.
Science ; 367(6478): 688-694, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029629

RESUMO

Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.


Assuntos
Proteínas do Sistema Complemento/fisiologia , Hipocampo/fisiologia , Transtornos da Memória/fisiopatologia , Memória de Longo Prazo/fisiologia , Microglia/fisiologia , Retenção Psicológica/fisiologia , Sinapses/fisiologia , Animais , Antígenos CD55 , Proteínas do Sistema Complemento/genética , Transtornos da Memória/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microglia/imunologia , Fagocitose
3.
Nat Commun ; 11(1): 986, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080187

RESUMO

Tissue microarchitecture and mechanics are important in development and pathologies of the Central Nervous System (CNS); however, their coordinating mechanisms are unclear. Here, we report that during colonization of the retina, microglia contacts the deep layer of high stiffness, which coincides with microglial bipolarization, reduction in TGFß1 signaling and termination of vascular growth. Likewise, stiff substrates induce microglial bipolarization and diminish TGFß1 expression in hydrogels. Both microglial bipolarization in vivo and the responses to stiff substrates in vitro require intracellular adaptor Kindlin3 but not microglial integrins. Lack of Kindlin3 causes high microglial contractility, dysregulation of ERK signaling, excessive TGFß1 expression and abnormally-patterned vasculature with severe malformations in the area of photoreceptors. Both excessive TGFß1 signaling and vascular defects caused by Kindlin3-deficient microglia are rescued by either microglial depletion or microglial knockout of TGFß1 in vivo. This mechanism underlies an interplay between microglia, vascular patterning and tissue mechanics within the CNS.


Assuntos
Microglia/fisiologia , Vasos Retinianos/inervação , Fator de Crescimento Transformador beta1/fisiologia , Actomiosina/fisiologia , Animais , Fenômenos Biomecânicos , Movimento Celular/fisiologia , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/fisiologia , Feminino , Hidrogéis , Integrinas/fisiologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Comunicação Parácrina , Retina/crescimento & desenvolvimento , Vasos Retinianos/citologia , Vasos Retinianos/crescimento & desenvolvimento , Fator de Crescimento Transformador beta1/genética
4.
Nat Commun ; 11(1): 264, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937758

RESUMO

Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.


Assuntos
Gânglios Espinais/imunologia , Macrófagos/fisiologia , Neuralgia/imunologia , Animais , Comunicação Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Hiperalgesia/imunologia , Imunossupressores/farmacologia , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microglia/metabolismo , Microglia/fisiologia , Traumatismos dos Nervos Periféricos/imunologia , Gravidez , Células Receptoras Sensoriais/metabolismo , Fatores Sexuais , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia
5.
Yakugaku Zasshi ; 139(11): 1385-1390, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685734

RESUMO

In neurodegenerative diseases, such as Alzheimer's disease (AD) and spinal cord injury (SCI), inhibited axonal regeneration lead to irreversible functional impairment. Although many agents that eliminate axonal growth impediments have been clinically investigated, none induced functional recovery. I hypothesized that the removal of impediments alone was not enough and that promoting axonal growth and neuronal network reconstruction were needed for recovery from neurodegenerative diseases. To promote axonal growth, I have focused on neurons and microglia. In vitro models of AD and SCI were developed by culturing neurons in the presence of amyloid ß (Aß) and chondroitin sulfate proteoglycan, respectively. These were then used to identify several extracts of herbal medicines and their constituents that promoted axonal growth. Oral administration of these extracts and their constituents improved memory and motor function in in vivo mouse models of AD and SCI, respectively. The bioactive compounds in these extracts were identified by analyzing brain and spinal cord samples from the mice. Their protein targets were identified using the drug affinity responsive target stability method. Analysis of early events in the axons after culture with Aß revealed that the inhibition of endocytosis was sufficient to prevent the axonal atrophy and memory deficits caused by Aß. The compounds that increased M2 microglia were observed to promote axonal normalization and growth; they were also found to recover memory and motor function in mice models of AD and SCI, respectively. The above results indicate that axonal growth plays important roles in the recovery from AD and SCI.


Assuntos
Axônios/fisiologia , Medicina Herbária , Regeneração Nervosa , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/farmacologia , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Estimulação Química
6.
Adv Exp Med Biol ; 1175: 129-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583587

RESUMO

Microglia constitute the major immune cells that permanently reside in the central nervous system (CNS) alongside neurons and other glial cells. These resident immune cells are critical for proper brain development, actively maintain brain health throughout the lifespan and rapidly adapt their function to the physiological or pathophysiological needs of the organism. Cutting-edge fate mapping and imaging techniques applied to animal models enabled a revolution in our understanding of their roles during normal physiological conditions. Here, we highlight studies that demonstrate the embryonic yolk sac origin of microglia and describe factors, including crosstalk with the periphery and external environment, that regulate their differentiation, homeostasis and function in the context of healthy CNS. The diversity of microglial phenotypes observed across the lifespan, between brain compartments and between sexes is also discussed. Understanding what defines specific microglial phenotypes is critical for the development of innovative therapies to modulate their effector functions and improve clinical outcomes.


Assuntos
Sistema Nervoso Central/citologia , Microglia/fisiologia , Animais , Encéfalo , Homeostase , Humanos , Saco Vitelino/citologia
7.
Nat Neurosci ; 22(11): 1771-1781, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636449

RESUMO

Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C/genética , Clozapina/análogos & derivados , Clozapina/farmacologia , Isoflurano/farmacologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microinjeções , Muscimol/farmacologia , Norepinefrina/farmacologia , Optogenética , Propanolaminas/farmacologia , Propranolol/farmacologia , Receptores Purinérgicos P2Y12/genética , Privação Sensorial/fisiologia , Córtex Somatossensorial/efeitos dos fármacos , Tetrodotoxina/farmacologia , Vigília
8.
Nat Neurosci ; 22(11): 1782-1792, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636451

RESUMO

Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of ß2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of ß2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.


Assuntos
Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Norepinefrina/fisiologia , Córtex Visual/fisiologia , Animais , Benzilaminas/farmacologia , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Ritmo Circadiano/fisiologia , Clembuterol/farmacologia , Dexmedetomidina/farmacologia , Dominância Ocular , Feminino , Fentanila/farmacologia , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Nadolol/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Norepinefrina/metabolismo , Propanolaminas/farmacologia , Restrição Física/fisiologia , Terbutalina/farmacologia , Vigília , Ferimentos e Lesões/fisiopatologia
9.
Mol Biol (Mosk) ; 53(5): 790-798, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661478

RESUMO

Recently, much attention has been drawn to unraveling the mechanisms of neurodegenerative and neuroinflammatory disease pathogenesis. A special role in the development of neuropathologies is assigned to the interaction of the nervous and the immune systems. Microglia are the cells of the immune system that function as resident macrophages of the central nervous system (CNS) and are involved in the development of CNS, as well as in homeostatic interactions. Impaired microglia can contribute to neuroinflammation and neurodegeneration. With the help of genome editing technologies, the main paradigms in the development and functions of microglia have been addressed. At the same time, an understanding of the mechanisms of regulation of microglia in normal and pathological conditions is necessary to create an effective therapy aimed at treating various neurological diseases. This review focuses on recent findings on the origin of microglia, its regulatory role in the central nervous system, as well as its contribution to the development of neuroinflammation.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/fisiologia , Homeostase , Inflamação/patologia , Microglia/fisiologia , Doenças Neurodegenerativas/patologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Humanos , Inflamação/fisiopatologia , Microglia/citologia , Microglia/patologia , Doenças Neurodegenerativas/fisiopatologia
10.
Exp Eye Res ; 187: 107753, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408629

RESUMO

The retina is known to have a local renin-angiotensin system (RAS) and dysfunction in the RAS is often associated with diseases of the retinal vasculature that cause irreversible vision loss. Regulation of the retinal vasculature to meet the metabolic needs of the tissues occurs through a mechanism called neurovascular coupling, which is critical for maintaining homeostatic function and support for neurons. Neurovascular coupling is the process by which support cells, including glia, regulate blood vessel calibre and blood flow in response to neural activity. In retinal vascular diseases, this coupling mechanism is often disrupted. However, the role that angiotensin II (Ang II), the main effector peptide of the RAS, has in regulating both the retinal vasculature and neurovascular coupling is not fully understood. As components of the RAS are located on the principal neurons, glia and blood vessels of the retina, it is possible that Ang II has a role in regulating communication and function between these three cell types, and therefore the capacity to regulate neurovascular coupling. This review focuses on components of the RAS located on the retinal neurovascular unit, and the potential of this system to contribute to blood flow modulation in the healthy and compromised retina.


Assuntos
Retinopatia Diabética/fisiopatologia , Microglia/fisiologia , Sistema Renina-Angiotensina/fisiologia , Vasos Retinianos/fisiologia , Angiotensina II/fisiologia , Animais , Humanos
11.
J Toxicol Sci ; 44(7): 471-479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270303

RESUMO

M1-microglia (neurotoxic microglia) regulate neuronal development and cell death and are involved in many pathologies in the brain. Although organotypic brain slice cultures are widely used to study the crosstalk between neurons and microglia, little is known about the properties of microglia in the mouse cerebral cortex slices. Here, we aimed to optimize the mouse cerebral slice cultures that reflect microglial functions and evaluate the effects of neurotoxic metals on M1-microglial activation. Most microglia in the cerebral slices prepared from postnatal day (P) 7 mice were similar to mature microglia in adult mice brains, but those in the slices prepared from P2 mice were immature, which is a conventional preparation condition. The degree of expression of M1-microglial markers (CD16 and CD32) and inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) by lipopolysaccharide, a representative microglia activator, in the cerebral slices of P7 mice were higher than that in the slices of P2 mice. These results indicate that M1-microglial activation can be evaluated more accurately in the cerebral slices of P7 mice than in those of P2 mice. Therefore, we next examined the effects of various neurotoxic metals on M1-microglial activation using the cerebral slices of P7 mice and found that methylmercury stimulated the activation to M1-microglia, but arsenite, lead, and tributyltin did not induce such activation. Altogether, the optimized mouse cerebral slice cultures used in this study can be a helpful tool to study the influence of various chemicals on the central nervous system in the presence of functionally mature microglia.


Assuntos
Córtex Cerebral/citologia , Metais/toxicidade , Microglia/efeitos dos fármacos , Microglia/fisiologia , Animais , Animais Recém-Nascidos , Arsenitos/toxicidade , Células Cultivadas , Córtex Cerebral/metabolismo , Citocinas/metabolismo , Expressão Gênica , Mediadores da Inflamação/metabolismo , Chumbo/toxicidade , Compostos de Metilmercúrio/toxicidade , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurônios/fisiologia , Receptores de IgG/genética , Receptores de IgG/metabolismo , Compostos de Trialquitina/toxicidade
12.
Mediators Inflamm ; 2019: 7651383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281228

RESUMO

Many patients experience excellent physical recoveries after surgery; however, there are some of them who from suffer mood fluctuation, even depression. Postoperative depression may be resulted from cognitive dysfunction, pain, and a compromised immune system during the surgery. But there is a higher possibility that general anaesthesia may be responsible for the development of depression. Here, we employed one of the most used anaesthetics, propofol, in a mouse model to investigate whether this intravenous anaesthetic compound could cause depressive-like behavioural performance in mice. We found a single dose of propofol caused significant abnormal behavioural performance in tail suspension, forced swimming, and open field tests. We also examined the brain section of these mice and revealed that there was significant reduced expression of the CD11b protein, which demonstrated an inhibition of propofol on microglial function. We investigated the effect of propofol on synaptic protein, SYP, and found there was no notable influence on the protein expression. These above results suggested that propofol treatment might promote the depressive-like behaviours in mice via influencing the microglial cell function. Furthermore, we found the level of the IL-6 cytokine was significantly increased in the brain tissue, which might subsequently cause the activation of the transcriptional factor, STAT3. Our finding may provide a new perspective of further understanding the mechanism of anaesthetic drugs and deciphering the underlying mechanism of postoperative depression.


Assuntos
Depressão/induzido quimicamente , Microglia/efeitos dos fármacos , Microglia/fisiologia , Propofol/efeitos adversos , Anestesia Intravenosa , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Antígeno CD11b/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Sinaptofisina/metabolismo
13.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311135

RESUMO

Many cell types express an acid-sensitive outwardly rectifying (ASOR) anion current of an unknown function. We characterized such a current in BV-2 microglial cells and then studied its interrelation with the volume-sensitive outwardly rectifying (VSOR) Cl- current and the effect of acidosis on cell volume regulation. We used patch clamp, the Coulter method, and the pH-sensitive dye BCECF to measure Cl- currents and cell membrane potentials, mean cell volume, and intracellular pH, respectively. The ASOR current activated at pH ≤ 5.0 and displayed an I- > Cl- > gluconate- permeability sequence. When compared to the VSOR current, it was similarly sensitive to DIDS, but less sensitive to DCPIB, and insensitive to tamoxifen. Under acidic conditions, the ASOR current was the dominating Cl- conductance, while the VSOR current was apparently inactivated. Acidification caused cell swelling under isotonic conditions and prevented the regulatory volume decrease under hypotonicity. We conclude that acidification, associated with activation of the ASOR- and inactivation of the VSOR current, massively impairs cell volume homeostasis. ASOR current activation could affect microglial function under acidotoxic conditions, since acidosis is a hallmark of pathophysiological events like inflammation, stroke or ischemia and migration and phagocytosis in microglial cells are closely related to cell volume regulation.


Assuntos
Canais de Cloreto/metabolismo , Microglia/metabolismo , Potenciais de Ação , Animais , Linhagem Celular , Cloretos/metabolismo , Concentração de Íons de Hidrogênio , Iodo/metabolismo , Transporte de Íons , Camundongos , Microglia/fisiologia , Pressão Osmótica
14.
Sci Total Environ ; 689: 662-678, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279213

RESUMO

Microcystin-leucine-arginine (MC-LR), which produced by toxic cyanobacteria and widely present in eutrophic waters, has been shown to have potent acute hepatotoxicity. MC-LR has been revealed to inflict damage to brain, while the neurotoxicity of chronic exposure to MC-LR and mechanisms underlying it are still confusing. Here, the mice were exposed to MC-LR dissolved in drinking water at dose of 1, 7.5, 15, and 30 µg/L for consecutive 180 days. MC-LR accumulated in mouse brains and impaired the blood-brain barrier by inducing the expression of matrix metalloproteinase-8 (MMP-8), which was regulated by NF-κB, c-Fos and c-Jun. Furthermore, MC-LR exposure induced microglial and astrocyte activation and resultant neuroinflammatory response. This study highlights the risks to human health of the current microcystin exposure.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Inflamação/fisiopatologia , Microcistinas/toxicidade , Junções Íntimas/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/fisiologia , Junções Íntimas/metabolismo
15.
Nat Rev Neurol ; 15(9): 540-555, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324897

RESUMO

Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical inflammation, microglial activation, astrogliosis and differential expression of inflammation-related proteins in the periphery. Furthermore, an overlap between FTD and autoimmune disease has been identified. The most substantial evidence, however, comes from genetic studies, and several FTD-related genes are also implicated in neuroinflammation. This Review discusses specific evidence of neuroinflammatory mechanisms in FTD and describes how advances in our understanding of these mechanisms, in FTD as well as in other neurodegenerative diseases, might facilitate the development and implementation of diagnostic tools and disease-modifying treatments for FTD.


Assuntos
Encefalite/fisiopatologia , Demência Frontotemporal/fisiopatologia , Animais , Encéfalo/imunologia , Encéfalo/fisiopatologia , Encefalite/complicações , Encefalite/imunologia , Demência Frontotemporal/complicações , Demência Frontotemporal/imunologia , Humanos , Microglia/imunologia , Microglia/fisiologia
16.
Curr Opin Anaesthesiol ; 32(5): 668-673, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31343465

RESUMO

PURPOSE OF REVIEW: Persistent postoperative pain (PPP) is a significant source of morbidity in our population. An excellent opportunity to understand the transition from acute to chronic pain states. Understanding the mechanisms that drive this and modulators that influence this transition is essential to both prevent and manage this condition. RECENT FINDINGS: Although the exact mechanism for the development of PPP is still poorly understood, hypotheses abound. Basic science research with animal models implicates nociceptive and neuropathic pain signals leading to pain sensitization due to persistent noxious signaling. Effects on the inhibitory modulation of noxious signaling in medullary-spinal pathways and descending modulation have also been implicated. SUMMARY: Persistent maladaptive neuroplastic changes secondary to neurotrophic factors and interactions between neurons and microglia may well explain the phenomenon. This article reviews the current thought processes on mechanisms and modulators from a basic science and epidemiological perspective.


Assuntos
Dor Crônica/etiologia , Neuralgia/etiologia , Nociceptividade/fisiologia , Dor Pós-Operatória/etiologia , Animais , Dor Crônica/fisiopatologia , Dor Crônica/terapia , Modelos Animais de Doenças , Humanos , Bulbo/citologia , Bulbo/fisiopatologia , Microglia/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiopatologia , Neuralgia/fisiopatologia , Neuralgia/terapia , Neurônios/fisiologia , Dor Pós-Operatória/fisiopatologia , Dor Pós-Operatória/terapia , Medula Espinal/citologia , Medula Espinal/fisiopatologia , Fatores de Tempo
17.
Nat Rev Neurol ; 15(8): 447-458, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31256193

RESUMO

Microglia are resident macrophages of the CNS that are involved in its development, homeostasis and response to infection and damage. Microglial activation is a common feature of neurological disorders, and although in some instances this activation can be damaging, protective and regenerative functions of microglia have been revealed. The most prominent example of the regenerative functions is a role for microglia in supporting regeneration of myelin after injury, a process that is critical for axonal health and relevant to numerous disorders in which loss of myelin integrity is a prevalent feature, such as multiple sclerosis, Alzheimer disease and motor neuron disease. Although drugs that are intended to promote remyelination are entering clinical trials, the mechanisms by which remyelination is controlled and how microglia are involved are not completely understood. In this Review, we discuss work that has identified novel regulators of microglial activation - including molecular drivers, population heterogeneity and turnover - that might influence their pro-remyelination capacity. We also discuss therapeutic targeting of microglia as a potential approach to promoting remyelination.


Assuntos
Sistema Nervoso Central/fisiologia , Doenças Desmielinizantes/fisiopatologia , Microglia/fisiologia , Remielinização , Envelhecimento , Animais , Sistema Nervoso Central/fisiopatologia , Doenças Desmielinizantes/terapia , Homeostase , Humanos , Ativação de Macrófagos
18.
Oxid Med Cell Longev ; 2019: 5123565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198491

RESUMO

Despite the fact that harboring the apolipoprotein E4 (APOE4) allele represents the single greatest risk factor for late-onset Alzheimer's disease (AD), the exact mechanism by which apoE4 contributes to disease progression remains unknown. Recently, we demonstrated that a 151 amino-terminal fragment of apoE4 (nApoE41-151) localizes within the nucleus of microglia in the human AD brain, suggesting a potential role in gene expression. In the present study, we investigated this possibility utilizing BV2 microglia cells treated exogenously with nApoE41-151. The results indicated that nApoE41-151 leads to morphological activation of microglia cells through, at least in part, the downregulation of a novel ER-associated protein, CXorf56. Moreover, treatment of BV2 cells with nApoE41-151 resulted in a 68-fold increase in the expression of the inflammatory cytokine, TNFα, a key trigger of microglia activation. In this regard, we also observed a specific binding interaction of nApoE41-151 with the TNFα promoter region. Collectively, these data identify a novel gene-regulatory pathway involving CXorf56 that may link apoE4 to microglia activation and inflammation associated with AD.


Assuntos
Apolipoproteína E4/metabolismo , Regulação da Expressão Gênica , Microglia/fisiologia , Fragmentos de Peptídeos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apolipoproteína E4/genética , Astrócitos/citologia , Astrócitos/fisiologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Camundongos , Microglia/citologia , Fragmentos de Peptídeos/genética , Fatores de Transcrição/genética
19.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182619

RESUMO

Toxoplasma gondii, a common neurotropic parasite, is increasingly being linked to neuropsychiatric disorders, including schizophrenia, Alzheimer's disease, and Parkinson's disease. However, the pathogenic mechanisms underlying these associations are not clear. Toxoplasma can reside in the brain for extensive periods in the form of tissue cysts, and this process requires a continuous immune response to prevent the parasite's reactivation. Because neuroinflammation may promote the onset and progression of neurodegenerative diseases, we investigated neurodegeneration-associated pathological changes in a mouse model of chronic Toxoplasma infection. Under conditions of high-grade chronic infection, we documented the presence of neurodegeneration in specific regions of the prefrontal cortex, namely, the anterior cingulate cortex (ACC) and somatomotor cortex (SC). Neurodegeneration occurred in both glutamatergic and GABAergic neurons. Neurons that showed signs of degeneration expressed high levels of CX3CL1, were marked by profoundly upregulated complement proteins (e.g., C1q and C3), and were surrounded by activated microglia. Our findings suggest that chronic Toxoplasma infection leads to cortical neurodegeneration and results in CX3CL1, complement, and microglial interactions, which are known to mediate the phagocytic clearance of degenerating neurons. Our study provides a mechanistic explanation for the link between Toxoplasma infection and psychiatric disorders.


Assuntos
Encéfalo/parasitologia , Ativação do Complemento/fisiologia , Microglia/fisiologia , Doenças Neurodegenerativas/etiologia , Toxoplasmose/complicações , Animais , Quimiocina CX3CL1/fisiologia , Doença Crônica , Modelos Animais de Doenças , Feminino , Camundongos , Ácido gama-Aminobutírico/fisiologia
20.
Nat Neurosci ; 22(7): 1046-1052, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182869

RESUMO

Failed regeneration of CNS myelin contributes to clinical decline in neuroinflammatory and neurodegenerative diseases, for which there is an unmet therapeutic need. Here we reveal that efficient remyelination requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state. We propose that impaired microglia death and/or repopulation may underpin dysregulated microglia activation in neurological diseases, and we reveal therapeutic targets to promote white matter regeneration.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Microglia/fisiologia , Regeneração Nervosa/fisiologia , Animais , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Doenças Desmielinizantes/induzido quimicamente , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/classificação , Esclerose Múltipla/patologia , Necrose , Nestina/análise , Fagocitose , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA , Substância Branca/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA