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1.
Glia ; 71(1): 71-90, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36222019

RESUMO

Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an anti-inflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.


Assuntos
Microglia , Fármacos Neuroprotetores , Animais , Camundongos , Microglia/metabolismo , Endocanabinoides/farmacologia , Endocanabinoides/metabolismo , Transdução de Sinais , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia
2.
J Exp Med ; 220(1)2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36219197

RESUMO

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2 function impairs the microglial response to amyloid-ß (Aß) plaques, resulting in more diffuse Aß plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of Aß and tau pathologies in AD. Since genetically decreasing TREM2 function increases Aß-induced tau seeding, we hypothesized that chronically increasing TREM2 signaling would decrease amyloid-induced tau-seeding and spreading. Using a mouse model of amyloidosis in which AD-tau is injected into the brain to induce Aß-dependent tau seeding/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering Aß plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate Aß-induced tau pathology, which may have important clinical implications.


Assuntos
Doença de Alzheimer , Amiloidose , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Amiloide , Peptídeos beta-Amiloides , Amiloidose/patologia , Animais , Modelos Animais de Doenças , Microglia/patologia , Placa Amiloide/patologia
3.
Biochim Biophys Acta Mol Cell Res ; 1870(1): 119385, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36302463

RESUMO

Palmitic acid (PA), the most common statured fatty acid in diets, is involved in peripheral as well as central inflammation. The M1 polarization of microglia plays an important role in PA-induced neuroinflammation. However, it is still unclear on the key factor and molecule mechanism of microglial polarization among it. Thus, we investigated whether the release of self-DNA into the cytoplasm of microglia was a consequence of PA treatment, as in aortic endothelial cells and adipocytes. RT-qPCR and immunofluorescence were performed to detect the status of cytosolic DNA and microglial polarization after PA treatment. We found that the content of cytosolic nDNA rather than mtDNA increased after PA treatment and the M1 polarization of microglia was associated with this. Moreover, the knockdown of cGAS in BV2 microglial cells demonstrated that the cGAS-STING pathway is involved in polarization process. Our results revealed that nDNA and cGAS-STING pathway are critically involved in PA-induced microglial M1 polarization. This mechanism may pose a new insight on targeting microglia may be a promising way to mitigate diet-induced early neuroinflammation.


Assuntos
Microglia , Ácido Palmítico , Microglia/metabolismo , Ácido Palmítico/farmacologia , Ácido Palmítico/metabolismo , Células Endoteliais/metabolismo , Citosol/metabolismo , Transdução de Sinais , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , DNA Mitocondrial/metabolismo
4.
Behav Brain Res ; 437: 114131, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36174842

RESUMO

The Notch signaling pathway is mainly involved in the regulation of neural stem cell proliferation, survival and differentiation during the development of the central nervous system. As a neurodevelopmental disorder, autism is associated with an abnormal increase in the number of microglia in several brain regions. These findings suggest that the pathogenesis of autism may be related to the Notch signaling pathway and microglia. In this review, we discuss how Notch pathway activity leads to behavioral abnormalities such as learning and memory impairment by influencing neuronal biological activities. An increase in microglial protein synthesis and abnormal autophagy can affect synaptic development and lead to behavioral abnormalities, and all of these changes can lead to autism. Furthermore, the Notch signaling pathway regulates the activation and differentiation of microglia and promotes inflammatory responses, leading to the occurrence of autism. When excessive reactive oxygen species (ROS) secreted by microglia cannot be cleared by autophagy in a timely manner, Notch signaling pathway activity is affected, possibly further increasing susceptibility to autism. This review reveals the mechanism underlying the role of the Notch signaling pathway, microglia and their interaction in the pathogenesis of autism and provides a theoretical reference for targeted clinical therapies for autism.


Assuntos
Transtorno Autístico , Microglia , Humanos , Microglia/metabolismo , Transtorno Autístico/metabolismo , Transdução de Sinais/fisiologia , Neurônios , Sistema Nervoso Central
5.
Methods Mol Biol ; 2561: 43-62, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36399264

RESUMO

This chapter describes the core procedures that we have developed over the last two decades to isolate routinely the microglia from postmortem human brains. The method is suitable for brain slices consisting of both gray and white matter.The ability to concomitantly isolate vascular cells with glial cells provides the opportunity to investigate multiple cell types originating from the same donor. This represents a novel approach for -omics research, with the potential for discovering the shared or distinct molecular features among the glia and vascular cells from the same individual.


Assuntos
Microglia , Substância Branca , Humanos , Neuroglia , Encéfalo
6.
Methods Mol Biol ; 2561: 63-85, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36399265

RESUMO

In this protocol, we describe the specific steps required to prepare human postmortem brain samples for ultrastructural microglial analysis. A detailed procedure is provided to improve the ultrastructural quality of the samples, using aldehyde fixatives followed by immunoperoxidase staining of allograft inflammatory factor 1 (AIF1, also known as IBA1), a marker of myeloid cells, and cluster of differentiation 68 (CD68), a marker of phagolysosomal activity. Additionally, we describe an osmium-thiocarbohydrazide-osmium (OTO) post-fixation method that preserves and increases the contrast of cellular membranes in human postmortem brain samples, as well as the steps necessary to acquire scanning electron microscopy (SEM) images of microglial cell bodies. In the last section, we cover the quantitative analysis of various microglial cytoplasmic organelles and their interactions with other parenchymal elements.


Assuntos
Encéfalo , Microglia , Humanos , Microglia/ultraestrutura , Microscopia Eletrônica de Varredura , Autopsia , Fixadores
7.
Glia ; 71(1): 103-126, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35353392

RESUMO

The discovery of cannabinoid receptors as the primary molecular targets of psychotropic cannabinoid Δ9 -tetrahydrocannabinol (Δ9 -THC) in late 1980s paved the way for investigations on the effects of cannabis-based therapeutics in brain pathology. Ever since, a wealth of results obtained from studies on human tissue samples and animal models have highlighted a promising therapeutic potential of cannabinoids and endocannabinoids in a variety of neurological disorders. However, clinical success has been limited and major questions concerning endocannabinoid signaling need to be satisfactorily addressed, particularly with regard to their role as modulators of glial cells in neurodegenerative diseases. Indeed, recent studies have brought into the limelight diverse, often unexpected functions of astrocytes, oligodendrocytes, and microglia in brain injury and disease, thus providing scientific basis for targeting glial cells to treat brain disorders. This Review summarizes the current knowledge on the molecular and cellular hallmarks of endocannabinoid signaling in glial cells and its clinical relevance in neurodegenerative and chronic inflammatory disorders.


Assuntos
Encefalopatias , Canabinoides , Animais , Humanos , Endocanabinoides , Canabinoides/farmacologia , Receptores de Canabinoides/fisiologia , Dronabinol , Microglia
8.
Phytomedicine ; 108: 154486, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36240609

RESUMO

BACKGROUND: Microglia are innate immune cells in the central nervous system that play a crucial role in neuroprotection by releasing neurotrophic factors, removing pathogens through phagocytosis, and regulating brain homeostasis. The constituents extracted from the roots and stems of the Daphne genkwa plant have shown neuroprotective effects in an animal model of Parkinson's disease. However, the effect of Daphne genkwa plant extract on microglia has yet to be demonstrated. PURPOSE: To study the anti-inflammatory and neuroprotective effects of Daphne genkwa flower extract (GFE) in microglia and explore the underlying mechanisms. METHODS: In-vitro mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase, Arginase1, and brain derived neurotropic factor (BDNF) were analyzed by reverse transcription polymerase chain reaction in microglia cells. Nitric oxide (NO) and TNF-α protein were respectively analyzed by Griess reagent and Enzyme Linked Immunosorbent Assay. Immunoreactivity of Iba-1, Neu-N, and BDNF in mouse brain were analyzed by immunofluorescence staining. Phagocytosis capacity of microglia was examined using fluorescent zymosan-red particles. RESULTS: GFE significantly inhibited lipopolysaccharide (LPS)-induced neuroinflammation and promoted neuroprotection both in vitro and in vivo. First, GFE inhibited the LPS-induced inflammatory factors NO, iNOS, and TNF-α in microglial cell lines and primary glial cells, thus demonstrating anti-inflammatory effects. Arginase1 and BDNF mRNA levels were increased in primary glial cells treated with GFE. Phagocytosis was also increased in microglia treated with GFE, suggesting a neuroprotective effect of GFE. In vivo, neuroprotective and anti-neuroinflammatory effects of GFE were also found in the mouse brain, as oral administration of GFE significantly inhibited LPS-induced neuronal loss and inflammatory activation of microglia. CONCLUSION: GFE has anti-inflammatory effects and promotes microglial neuroprotective effects. GFE inhibited the pro-inflammatory mediators and enhanced neuroprotective microglia activity by increasing BDNF expression and phagocytosis. These novel findings of the GFE effect on microglia show an innovative approach that can potentially promote neuroprotection for the prevention of neurodegenerative diseases.


Assuntos
Daphne , Fármacos Neuroprotetores , Extratos Vegetais , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Daphne/química , Flores/química , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Neurosci Lett ; 792: 136968, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36396023

RESUMO

Alzheimer's disease (AD) patients frequently experience neuropsychiatric symptoms (NPS), which are linked to a lower quality of life and a faster rate of disease progression. A growing body of research indicates that several microglial phenotypes control the inflammatory response and are crucial in the pathophysiology of AD-related NPS. Given the crucial role played by inflammatory mediators produced by microglia in developing of NPS, interferon-beta (IFNß), a cytokine with anti-inflammatory capabilities, maybe a successful treatment for NPS caused by AD. In this investigation, using a rat model of AD, we examined the impact of intranasal treatment of IFNß on anxious/depressive-like behavior and microglial M1/M2 polarization. The rat hippocampus was bilaterally injected with lentiviruses harboring mutant human amyloid precursor protein. Rats were given recombinant IFNß1a (68,000 IU/rat) via the intranasal route, starting on day 23 following viral infection and continuing until day 49. On days 47-49, the elevated plus maze, forced swim, and tail suspension tests were applied to measure anxiety- and depressive-like behavior. Additionally, qPCR was utilized to quantify the expression of M1 markers (CD68, CD86, and CD40) and M2 markers (Ym1, CD206, Arg1, GDNF, BDNF, and SOCS1). Our findings demonstrated that decreased M2 marker expression is accompanied by anxious/depressive-like behavior when the mutant human APP gene is overexpressed in the hippocampus. In the rat model of AD, IFNß therapy reduces anxious/depressive-like behaviors, at least in part by polarizing microglia towards M2. Therefore, IFNß may be a viable therapeutic drug for reducing NPS in the context of AD.


Assuntos
Doença de Alzheimer , Microglia , Animais , Humanos , Ratos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Ansiedade/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Interferon beta , Microglia/metabolismo , Qualidade de Vida , Depressão/tratamento farmacológico
10.
Life Sci Alliance ; 6(2)2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36450444

RESUMO

Microglial phagocytosis and clearance are important for the removal of amyloid-ß (Aß) plaques in Alzheimer's disease (AD). Chronic exposure of microglia to Aß plaques leads to microglial metabolic dysfunction, and dysregulation of microglia can accelerate the deposition of Aß plaques and cause learning and memory impairment. Thus, regulating microglial Aß clearance is crucial for the development of therapeutics for AD-related dementia. Here, Down syndrome critical region 1 (DSCR1) deficiency ameliorated Aß plaque deposition in the 5xFAD mouse model of AD by altering microglial activity; however, the Aß synthesis pathway was not affected. DSCR1 deficiency improved spatial learning and memory impairment in 5xFAD mice. Furthermore, DSCR1-deficient microglia exhibited accelerated lysosomal degradation of Aß after phagocytosis, and BV2 cells with stable knockdown of DSCR1 demonstrated enhanced lysosomal activity. RNA-sequencing analysis showed that the transcriptional signatures associated with responses to IFN-γ were significantly up-regulated in DSCR1-knockdown BV2 cells treated with Aß. Our data strongly suggest that DSCR1 is a critical mediator of microglial degradation of amyloid plaques and a new potential microglial therapeutic target in AD.


Assuntos
Doença de Alzheimer , Síndrome de Down , Animais , Camundongos , Doença de Alzheimer/genética , Microglia , Peptídeos beta-Amiloides , Placa Amiloide , Proteínas de Ligação ao Cálcio , Proteínas Musculares
11.
J Exp Med ; 220(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36399126

RESUMO

In this important study, Jain et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220654) find that chronic TREM2 activation by AL002a antibody exacerbates the seeding and spread of pathological tau, enhances the disease-associated microglial signature, and increases neurite dystrophy in 5xFAD mice seeded with Alzheimer's disease tau.


Assuntos
Doença de Alzheimer , Doença Enxerto-Hospedeiro , Animais , Camundongos , Humanos , Amigos , Doença de Alzheimer/patologia , Microglia/patologia , Doença Enxerto-Hospedeiro/patologia , Glicoproteínas de Membrana , Receptores Imunológicos
12.
J Ethnopharmacol ; 302(Pt A): 115914, 2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36347303

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: As one of the important traditional Chinese medicines, Alpinia oxyphylla could warm and tonify the kidney and spleen. It has been used as anti-salivation, anti-diarrhea in various diseases. In recent years, many studies have reported the significant effect of Alpinia oxyphylla on improving cognitive ability, anti oxidative stress and protecting neurons. AIMS OF THE STUDY: In this paper, we studied whether AE and its main active components could improve M1 and M2 polarization, inhibit neuroinflammation through triggering receptor expressed on myeloid cells 2 (TREM2), and exert anti-inflammatory effects. MATERIALS AND METHODS: In this paper, the concentrations of inflammatory cytokines such as NO, TNF-α, IL-10 were assessed using detection kits respectively. Arg-1 and Iba-1, as polarized markers of M1 and M2, were detected by Immunofluorescence staining. CD86 and CD206 were tested by flow cytometry as surface markers of M1 and M2. Furthermore, RT-PCR was performed to determinate TNF-α, IL-10, Arg-1, and Iba-1. Western blot was used to test the activation of PI3K/AKT/GSK3ß and BDNF/TrkB/TLR4 signaling pathways. TREM2 siRNA treatment further verified the action target of Chrysin, the main active ingredient of Alpinia oxyphylla. Molecular docking study was performed to investigate the binding mode between Chrysin and the human TREM2. RESULTS: We found that AE could promote the phenotypic transformation of microglia from M1 to M2, and similar effects of Chrysin were observed. Furthermore, downregulation of TREM2 blocked the anti-neuroinflammation of Chrysin, and inhibited the shift of M1 phenotype to M2 phenotype. Additionally, TREM2-siRNA suppressed the effects of Chrysin on PI3K/AKT/GSK3ß and BDNF/TrkB/TLR4 signaling pathways. CONCLUSIONS: Our findings indicated that AE could improve the polarization response of microglia. TREM2 plays a vital role in the microglial repolarization effects of Chrysin through PI3K/AKT/GSK3ß and BDNF/TrkB/TLR4 signaling pathways regulated by neuroinflammation.


Assuntos
Lipopolissacarídeos , Microglia , Humanos , Lipopolissacarídeos/farmacologia , Interleucina-10/metabolismo , Receptor 4 Toll-Like/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , RNA Interferente Pequeno/farmacologia , Simulação de Acoplamento Molecular , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
13.
Zhen Ci Yan Jiu ; 47(11): 941-48, 2022 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-36453669

RESUMO

OBJECTIVE: To observe the effect of acupuncture on microglia polarization and inflammatory reaction in rats with cerebral ischemia-reperfusion injury (CIRI), so as to explore its mechanisms underlying improvement of CIRI. METHODS: Thirty male SD rats were randomly divided into sham operation, model, and acupuncture groups, with 10 rats in each group. The CIRI model was established by occlusion of the middle cerebral artery (MCAO) for 1 h, followed by reperfusion. After modeling, rats in the acupuncture group received manual acupuncture stimulation of "Dazhui" (GV14), "Baihui"(GV20), "Shuigou" (GV26), bilateral "Zusanli" (ST36) and "Fengchi" (GB20) by twirling the needles rapidly for 10 s/acupoint every 10 min, with the needles retained for 20 min. The treatment was conducted once daily for successive 7 days. The neurological function was evaluated according to Longa's method. The state of CIRI was observed after Nissl staining, and the expression levels of Iba-1, iNOS, Arg1, BDNF, GDNF and NeuN in the ischemic cortex tissue were detected by immunofluorescence staining. The contents of TNF-α, IL-6 and IL-10 in the ischemic tissue were assayed by ELISA. The protein expression levels of BDNF, GDNF, TLR4, MyD88 and NF-κB in the ischemic tissues were detected by Western blot. RESULTS: The neurological deficit score on the 24 h and 7th day was considerably higher in the model group than in the sham operation group (P<0.01), and evidently lower on the 7th day in the acupuncture group than in the model group (P<0.01). The number of NeuN positive cells,the area of immunofluorescence dual labelling of Arg1, BDNF and GDNF positive staining, IL-10 content, BDNF and GDNF protein expressions were significantly decreased (P<0.01), and the immunofluorescence dual labelling area of Iba-1 and iNOS, TNF-α and IL-6 contents, the pretein expression levels of TLR4, MyD88 and NF-κB considerably increased (P<0.01) in the model group relevant to the sham operation group. In contrast to the model group, the acupuncture group had a significant increase in the number of NeuN positive cells, the immunofluorescence dual labelling area of Arg1, BDNF and GDNF positive staining, IL-10 content, and BDNF and GDNF protein expressions (P<0.05, P<0.01), and an evident decrease in Iba-1 and iNOS positive staining, contents of TNF-α and IL-6, and the protein expression levels of TLR4, MyD88 and NF-κB (P<0.01, P<0.05). Nissl staining showed a marked reduction in the number of neurons, the nucleus pyknosis and nissl bodies and loose arrangement of the neuronal cells in the model group, which was relatively milder in the acupuncture group. CONCLUSION: Acupuncture intervention can improve neurological function in CIRI rats, which may be related to its effects in regulating the polarization of microglia, reducing inflammatory reaction and increasing the secretion of neurotrophic factors in the brain, inhibiting TLR4/MyD88/NF-κB signaling pathway.


Assuntos
Terapia por Acupuntura , Traumatismo por Reperfusão , Masculino , Animais , Ratos , Ratos Sprague-Dawley , Interleucina-10/genética , Microglia , NF-kappa B/genética , Fator de Necrose Tumoral alfa , Fator Neurotrófico Derivado do Encéfalo , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Interleucina-6 , Fator 88 de Diferenciação Mieloide/genética , Receptor 4 Toll-Like/genética , Infarto Cerebral , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/terapia
14.
Oxid Med Cell Longev ; 2022: 4564471, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308167

RESUMO

The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the efficacy of Omav in ICH. Omav significantly promoted Nrf2 nuclear accumulation and the expression of HO-1 and NQO1 in BV2 cells. In addition, both in vitro and in vivo experiments showed that Omav treatment inhibited M1-like activation and promoted the activation of the M2-like microglial phenotype. Omav inhibited OxyHb-induced ROS generation and preserved the function of mitochondria in BV2 cells. Intraperitoneal administration of Omav improved sensorimotor function in the ICH mouse model. Importantly, these effects were blocked by pretreatment with ML385, a selective inhibitor of Nrf2. Collectively, Omav modulated microglial polarization by activating Nrf2 and inhibiting ROS generation in ICH models, suggesting that it might be a promising drug candidate for the treatment of ICH.


Assuntos
Lesões Encefálicas , Microglia , Animais , Lesões Encefálicas/tratamento farmacológico , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Humanos , Camundongos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fenótipo , Triterpenos
15.
Neuron ; 110(21): 3497-3512, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36327896

RESUMO

CNS-resident macrophages-including parenchymal microglia and border-associated macrophages (BAMs)-contribute to neuronal development and health, vascularization, and tissue integrity at steady state. Border-patrolling mononuclear phagocytes such as dendritic cells and monocytes confer important immune functions to the CNS, protecting it from pathogenic threats including aberrant cell growth and brain malignancies. Even though we have learned much about the contribution of lymphocytes to CNS pathologies, a better understanding of differential roles of tissue-resident and -invading phagocytes is slowly emerging. In this perspective, we propose that in CNS neuroinflammatory diseases, tissue-resident macrophages (TRMs) contribute to the clearing of debris and resolution of inflammation, whereas blood-borne phagocytes are drivers of immunopathology. We discuss the remaining challenges to resolve which specialized mononuclear phagocyte populations are driving or suppressing immune effector function, thereby potentially dictating the outcome of autoimmunity or brain cancer.


Assuntos
Neoplasias Encefálicas , Sistema Fagocitário Mononuclear , Humanos , Microglia , Fagócitos/patologia , Macrófagos , Monócitos , Neoplasias Encefálicas/patologia
16.
Neuron ; 110(21): 3458-3483, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36327895

RESUMO

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.


Assuntos
Microglia
17.
Neuron ; 110(21): 3444-3457, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36327894

RESUMO

In the central nervous system (CNS), microglia carry out multiple tasks related to brain development, maintenance of brain homeostasis, and function of the CNS. Recent advanced in vitro model systems allow us to perform more detailed and specific analyses of microglial functions in the CNS. The development of human pluripotent stem cells (hPSCs)-based 2D and 3D cell culture methods, particularly advancements in brain organoid models, offers a better platform to dissect microglial function in various contexts. Despite the improvement of these methods, there are still definite restrictions. Understanding their drawbacks and benefits ensures their proper use. In this primer, we review current developments regarding in vitro microglial production and characterization and their use to address fundamental questions about microglial function in healthy and diseased states, and we discuss potential future improvements with a particular emphasis on brain organoid models.


Assuntos
Microglia , Células-Tronco Pluripotentes , Humanos , Microglia/fisiologia , Encéfalo/fisiologia , Sistema Nervoso Central , Homeostase
18.
Neuron ; 110(21): 3513-3533, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36327897

RESUMO

Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.


Assuntos
Doença de Alzheimer , Microglia , Humanos , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Estudo de Associação Genômica Ampla , Pool Gênico , Fagocitose/genética
19.
Biol Pharm Bull ; 45(11): 1699-1705, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36328505

RESUMO

Hydrogen sulfide and polysulfides are increasingly recognized as bioactive signaling molecules to produce various actions and regulate (patho)physiological processes. Here we examined the effects of sodium sulfide (Na2S) and sodium trisulfide (Na2S3) on an experimental model of intracerebral hemorrhage (ICH) in mice. Na2S or Na2S3 (25 µmol/kg, intraperitoneally (i.p.)) was administered 30 min before ICH induction by intrastriatal injection of collagenase. We found that Na2S significantly ameliorated sensorimotor functions of mice after ICH. Histopathological examinations revealed that Na2S inhibited neuron loss in the striatum, prevented axon degeneration in the internal capsule, and ameliorated axonal transport dysfunction in the striatum and the cerebral cortex where the edge of hematoma was located. Although Na2S did not suppress accumulation of activated microglia/macrophages in the peri-hematoma region, it suppressed ICH-induced upregulation of inflammatory mediators such as C-X-C motif ligand 2. On the other hand, Na2S3 did not ameliorate ICH-induced sensorimotor dysfunction. Although the effect of Na2S3 on several parameters such as axon degeneration and axonal transport dysfunction was comparable to that of Na2S, Na2S3 did not significantly inhibit neuron loss and upregulation of inflammatory mediators. These results suggest that the regulation of multiple pathological events is involved in the effect of Na2S leading to amelioration of neurological symptoms associated with ICH.


Assuntos
Hemorragia Cerebral , Microglia , Camundongos , Animais , Hemorragia Cerebral/tratamento farmacológico , Modelos Teóricos , Hematoma/complicações , Mediadores da Inflamação/farmacologia
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