Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 94
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Immunity ; 54(7): 1594-1610.e11, 2021 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-34174183

RESUMEN

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.


Asunto(s)
Encéfalo/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Microglía/inmunología , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/metabolismo , Encéfalo/patología , Linfocitos T CD8-positivos/metabolismo , COVID-19/patología , Comunicación Celular , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Humanos , Proteínas de Punto de Control Inmunitario/metabolismo , Inflamación , Activación de Linfocitos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Bulbo Olfatorio/inmunología , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/patología , Insuficiencia Respiratoria/inmunología , Insuficiencia Respiratoria/patología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
2.
Immunity ; 48(3): 514-529.e6, 2018 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-29548672

RESUMEN

Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically.


Asunto(s)
Histona Desacetilasa 1/genética , Histona Desacetilasa 2/genética , Homeostasis , Microglía/inmunología , Microglía/metabolismo , Enfermedades Neurodegenerativas/genética , Neurogénesis/genética , Animales , Apoptosis , Proliferación Celular , Modelos Animales de Enfermedad , Epigénesis Genética , Expresión Génica , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Histonas/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/psicología , Neurogénesis/inmunología , Fagocitosis/inmunología , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Aprendizaje Espacial , Transcriptoma
3.
Immunity ; 46(6): 1030-1044.e8, 2017 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-28636953

RESUMEN

Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.


Asunto(s)
Hipocampo/metabolismo , MicroARNs/genética , Microglía/fisiología , Neuronas/fisiología , Ribonucleasa III/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Reparación del ADN , Femenino , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Humanos , Imagenología Tridimensional , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/metabolismo , Actividad Motora , Plasticidad Neuronal , Ribonucleasa III/genética
4.
EMBO J ; 40(23): e108605, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34622466

RESUMEN

The immune cells of the central nervous system (CNS) comprise parenchymal microglia and at the CNS border regions meningeal, perivascular, and choroid plexus macrophages (collectively called CNS-associated macrophages, CAMs). While previous work has shown that microglial properties depend on environmental signals from the commensal microbiota, the effects of microbiota on CAMs are unknown. By combining several microbiota manipulation approaches, genetic mouse models, and single-cell RNA-sequencing, we have characterized CNS myeloid cell composition and function. Under steady-state conditions, the transcriptional profiles and numbers of choroid plexus macrophages were found to be tightly regulated by complex microbiota. In contrast, perivascular and meningeal macrophages were affected to a lesser extent. An acute perturbation through viral infection evoked an attenuated immune response of all CAMs in germ-free mice. We further assessed CAMs in a more chronic pathological state in 5xFAD mice, a model for Alzheimer's disease, and found enhanced amyloid beta uptake exclusively by perivascular macrophages in germ-free 5xFAD mice. Our results aid the understanding of distinct microbiota-CNS macrophage interactions during homeostasis and disease, which could potentially be targeted therapeutically.


Asunto(s)
Enfermedad de Alzheimer/inmunología , Bacterias/crecimiento & desarrollo , Sistema Nervioso Central/inmunología , Homeostasis , Macrófagos/inmunología , Células Mieloides/inmunología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/microbiología , Enfermedad de Alzheimer/patología , Animales , Bacterias/clasificación , Bacterias/metabolismo , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/microbiología , Sistema Nervioso Central/patología , Femenino , Macrófagos/metabolismo , Macrófagos/microbiología , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota , Células Mieloides/metabolismo , Células Mieloides/microbiología , Células Mieloides/patología , Transcriptoma
5.
Immunity ; 44(4): 901-12, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-27096319

RESUMEN

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.


Asunto(s)
Encéfalo/citología , Quimiocina CXCL10/inmunología , Trastornos del Conocimiento/genética , Células Endoteliales/inmunología , Células Epiteliales/inmunología , Conducta de Enfermedad/fisiología , Receptor de Interferón alfa y beta/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Encéfalo/inmunología , Comunicación Celular/inmunología , Células Cultivadas , Trastornos del Conocimiento/psicología , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/metabolismo , Endotelio/citología , Endotelio/inmunología , Epitelio/inmunología , Interferón Tipo I/uso terapéutico , Helicasa Inducida por Interferón IFIH1 , Masculino , Ratones , ARN Bicatenario/genética , Receptor de Interferón alfa y beta/inmunología , Receptores CXCR3/inmunología , Transducción de Señal/inmunología , Virosis/inmunología
6.
Acta Neuropathol ; 148(1): 11, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39060438

RESUMEN

The underlying pathogenesis of neurological sequelae in post-COVID-19 patients remains unclear. Here, we used multidimensional spatial immune phenotyping and machine learning methods on brains from initial COVID-19 survivors to identify the biological correlate associated with previous SARS-CoV-2 challenge. Compared to healthy controls, individuals with post-COVID-19 revealed a high percentage of TMEM119+P2RY12+CD68+Iba1+HLA-DR+CD11c+SCAMP2+ microglia assembled in prototypical cellular nodules. In contrast to acute SARS-CoV-2 cases, the frequency of CD8+ parenchymal T cells was reduced, suggesting an immune shift toward innate immune activation that may contribute to neurological alterations in post-COVID-19 patients.


Asunto(s)
Encéfalo , COVID-19 , Inmunidad Innata , Humanos , COVID-19/inmunología , Inmunidad Innata/inmunología , Encéfalo/inmunología , Encéfalo/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Microglía/inmunología , Microglía/patología , Adulto , Linfocitos T CD8-positivos/inmunología , SARS-CoV-2/inmunología , Cicatriz/inmunología , Cicatriz/patología , Aprendizaje Automático
7.
Immunity ; 43(1): 92-106, 2015 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-26163371

RESUMEN

During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the organism's lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion. Microglia repopulation relied on CNS-resident cells, independent from bone-marrow-derived precursors. During repopulation, microglia formed clusters of highly proliferative cells that migrated apart once steady state was achieved. Proliferating microglia expressed high amounts of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Hence, microglia have the potential for efficient self-renewal without the contribution of peripheral myeloid cells, and IL-1R signaling participates in this restorative proliferation process.


Asunto(s)
Células Madre Hematopoyéticas/citología , Macrófagos/citología , Microglía/citología , Receptores Tipo I de Interleucina-1/biosíntesis , Animales , Secuencia de Bases , Células de la Médula Ósea/inmunología , Receptor 1 de Quimiocinas CX3C , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Sistema Nervioso Central/citología , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptores de Quimiocina/genética , Receptores Tipo I de Interleucina-1/antagonistas & inhibidores , Análisis de Secuencia de ADN , Transducción de Señal , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética
8.
Nature ; 556(7701): 332-338, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29643512

RESUMEN

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral ß-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.


Asunto(s)
Encéfalo/inmunología , Encéfalo/patología , Inmunidad Innata , Memoria Inmunológica , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/patología , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Amiloidosis/inmunología , Amiloidosis/patología , Animales , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Tolerancia Inmunológica , Inflamación/genética , Inflamación/inmunología , Masculino , Ratones , Microglía/inmunología , Microglía/metabolismo , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/patología
9.
Nature ; 549(7672): 389-393, 2017 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-28854169

RESUMEN

The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.


Asunto(s)
Células Precursoras Eritroides/patología , Sistema de Señalización de MAP Quinasas , Mutación , Células Progenitoras Mieloides/patología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Animales , Células Clonales/enzimología , Células Clonales/metabolismo , Células Clonales/patología , Modelos Animales de Enfermedad , Células Precursoras Eritroides/enzimología , Células Precursoras Eritroides/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Histiocitosis/enzimología , Histiocitosis/genética , Histiocitosis/metabolismo , Histiocitosis/patología , Humanos , Macrófagos/enzimología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Microglía/enzimología , Microglía/metabolismo , Microglía/patología , Mosaicismo , Células Progenitoras Mieloides/enzimología , Células Progenitoras Mieloides/metabolismo , Enfermedades Neurodegenerativas/enzimología , Enfermedades Neurodegenerativas/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo
10.
EMBO J ; 37(2): 167-182, 2018 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-29229786

RESUMEN

Alzheimer's disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid-ß (Aß), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aß can be initiated by prion-like seeding, the impact and functional consequences of induced Aß deposits (Aß seeding) on neurons still remain open questions. Here, we find that Aß seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aß deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aß seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aß seeding and the consequences thereof and attributes microglia an important role in diminishing Aß seeding by environmental enrichment.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proliferación Celular , Microglía/metabolismo , Fagocitosis , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/genética , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Microglía/patología
11.
Depress Anxiety ; 39(5): 387-396, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35421280

RESUMEN

BACKGROUND: Early-onset (EO) major depressive disorder (MDD) patients experience more depressive episodes and an increased risk of relapse. Thus, on a neurobiological level, adult EO patients might display brain structure and function different from adult-onset (AO) patients. METHODS: A total of 103 patients (66 females) underwent magnetic resonance imaging. Structural measures of gray matter volume (GMV) and functional connectivity networks during resting state were compared between EO (≤19 years) and AO groups. Four residual major depression symptoms, mood, anxiety, insomnia, and somatic symptoms, were correlated with GMV between groups. RESULTS: We found comparatively increased GMV in the EO group, namely the medial prefrontal and insular cortex, as well as the anterior hippocampus. Functional networks in EO patients showed a comparatively weaker synchronization of the left hippocampus with the adjacent amygdala, and a stronger integration with nodes in the contralateral prefrontal cortex and supramarginal gyrus. Volumetric analysis of depression symptoms associated the caudate nuclei with symptoms of insomnia, and persisting mood symptoms with the right amygdala, while finding no significant clusters for somatic and anxiety symptoms. CONCLUSIONS: The study highlights the important role of the hippocampus and the prefrontal cortex in EO patients as part of emotion-regulation networks. Results in EO patients demonstrated subcortical volume changes irrespective of sleep and mood symptom recovery, which substantiates adolescence as a pivotal developmental phase for MDD. Longitudinal studies are needed to differentiate neural recovery trajectories while accounting for age of onset.


Asunto(s)
Trastorno Depresivo Mayor , Trastornos del Inicio y del Mantenimiento del Sueño , Adolescente , Adulto , Encéfalo , Femenino , Sustancia Gris/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino
12.
Immunity ; 37(2): 264-75, 2012 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-22902234

RESUMEN

Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c(+) DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction of regulatory T cells. Our results show that a reduction of DCs interferes with tolerance, resulting in a stronger inflammatory response, and that other APC populations could compensate for the loss of immunogenic APC function in DC-depleted mice.


Asunto(s)
Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T Reguladores/inmunología , Animales , Presentación de Antígeno/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Antígeno CD11c , Células Dendríticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Reguladores/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
13.
Depress Anxiety ; 38(4): 447-455, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33131185

RESUMEN

BACKGROUND: Serious long term health and economic detriment accompany residual depressive symptoms even in fully remitted depressed patients (rMDD). Neurobiological predictors for rMDD patients' illness trajectory are absent. METHODS: rMDD patients (n = 39, female = 26) underwent magnetic resonance imaging. Baseline analyses of brain structure via voxel-based morphometry and brain function via functional connectivity (FC) at rest were correlated with changes in the Hamilton Depression Rating Scale between baseline and follow-up, and incidence of a recurrent major depressive episode (MDE) within a 2-year period. RESULTS: Gray matter increases in default mode (DN) regions in the posterior cingulate cortex (PCC) and increased resting-state FC within the DN both predicted change of depressive symptoms. Patients with recurrent MDE had larger bilateral nucleus accumbens and left insula volumes. Post hoc exploratory analysis of nucleus accumbens and insula conceptualized as part of the brain's reward circuit demonstrated reduced connectivity in patients with recurrent MDE. CONCLUSIONS: Higher DN connectivity and PCC volume coinciding with a more favorable course of symptoms suggest neural mechanisms of self-recovery beyond the phase of active medical treatment. Alterations in the brain's reward circuit might be a starting point for designing maintenance treatments that prevent recurrent MDEs in rMDD patients.


Asunto(s)
Trastorno Depresivo Mayor , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Trastorno Depresivo Mayor/diagnóstico por imagen , Femenino , Giro del Cíngulo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas
14.
Compr Psychiatry ; 102: 152196, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32927367

RESUMEN

INTRODUCTION: Unipolar depression is a common and debilitating disorder. Immunological explanatory approaches have become increasingly important in recent years and can be studied particularly well in the cerebrospinal fluid (CSF). Previous studies discerned alterations in interleukin (IL)-6 and IL-8 levels; however, findings regarding IL-8 were partly contradictory. The aim of the present study was to investigate the concentrations of different cytokines and chemokines, focusing on IL-8, in the CSF of patients with unipolar depression. MATERIALS AND METHODS: Participants included 40 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension. CSF cytokine levels were measured using a magnetic bead multiplexing immunoassay. RESULTS: IL-8 levels in the CSF of the patient group with depression were significantly higher than those in the control group (Mean ± SD: 38.44 ± 6.26 pg/ml versus 21.40 ± 7.96 pg/ml; p < .001). LIMITATIONS: The significance of the results is limited by the retrospective design and methodological aspects. DISCUSSION: The main findings of this study were significantly higher concentrations of IL-8 in the CSF of patients with unipolar depression than in the control group. The detection of high CSF IL-8 levels in this study supports the idea that inflammatory processes might play a role in the pathophysiology of a subgroup of patients with depression.


Asunto(s)
Trastorno Depresivo , Interleucina-8 , Quimiocinas , Citocinas , Trastorno Depresivo/diagnóstico , Humanos , Estudios Retrospectivos
15.
EMBO J ; 34(12): 1612-29, 2015 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-25896511

RESUMEN

Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.


Asunto(s)
Encéfalo/metabolismo , Endopeptidasas/deficiencia , Interferones/metabolismo , Microglía/metabolismo , Modelos Neurológicos , Transducción de Señal/fisiología , Animales , Western Blotting , Clonación Molecular , Cartilla de ADN/genética , Endopeptidasas/genética , Endopeptidasas/metabolismo , Técnicas Histológicas , Ratones , Ratones Noqueados , Análisis por Micromatrices , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Estadísticas no Paramétricas , Ubiquitina Tiolesterasa
16.
J Psychosoc Oncol ; 36(3): 350-363, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29424665

RESUMEN

PURPOSE: The objective was to explore the relationships among cognitive appraisals of prostate cancer (challenge, threat, and harm/loss), social comparisons, and quality of life in men previously diagnosed. Design, Sample, & Methods: Men who had participated in prostate cancer support groups completed a cross-sectional questionnaire (N = 189). Multivariable linear regression was used to evaluate social comparisons as mediators of quality of life while controlling for uncertainty and optimism. FINDINGS: Positive and negative social comparisons were parallel mediators of the relationships between challenge or threat appraisals and quality of life, while only negative social comparisons mediated the relationship between harm/loss appraisals and quality of life. CONCLUSIONS: These findings demonstrate the importance of social comparisons in accounting for the effect of cognitive appraisals of prostate cancer on quality of life among men in support groups. Implications for Psychosocial Providers: Interventions to improve quality of life could address reduction of maladaptive comparisons, a strategy that could be tailored based on the patient's appraisal of prostate cancer.


Asunto(s)
Neoplasias de la Próstata/psicología , Calidad de Vida/psicología , Grupos de Autoayuda , Percepción Social , Anciano , Estudios Transversales , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Encuestas y Cuestionarios
17.
Glia ; 65(9): 1397-1406, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28519900

RESUMEN

Type I interferons (IFNs), IFN-α and IFN-ß, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon-stimulated gene expression have been linked to several CNS diseases termed "interferonopathies" including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with virus-induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well-balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain 'interferonopathies'.


Asunto(s)
Sistema Nervioso Central/metabolismo , Homeostasis/fisiología , Interferón Tipo I/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Animales , Humanos
18.
Eur J Immunol ; 46(6): 1340-2, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27198084

RESUMEN

The antibacterial enzyme lysozyme M (LysM) encoded by the Lyz2 gene is broadly expressed in myeloblasts, macrophages, and neutrophils, and thus has been used for a long time as a cell-specific marker for myeloid cells in mice. In order to delete loxP-site flanked genes in myeloid cells, a Cre-recombinase (Cre) expressing mouse line was created by inserting Cre-coding sequence into the translational start site of the LysM gene. In this issue of the European Journal of Immunology [2016. 46: 1529-1532], Orthgiess et al. verify, with the help of tdTomato and YFP reporter mouse lines, LysM-driven recombination. Unexpectedly, the authors also describe major expression of the tdTomato reporter protein in brain neurons of the central nervous system (CNS), with only a very small percentage of gene recombination in myeloid cells of the brain, called microglia. These findings cause justified concerns regarding the efficient and specific targeting of microglia and peripheral myeloid cells using LysM-Cre mice and should stimulate thoughts on conclusions drawn from past experiments on the diseased CNS employing this Cre/loxP-deleter line.


Asunto(s)
Integrasas/genética , Células Mieloides , Animales , Marcación de Gen , Macrófagos/inmunología , Ratones , Ratones Transgénicos , Microglía , Neuronas , Proteínas/genética , Recombinación Genética
19.
Trends Immunol ; 35(4): 139-40, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24636251

RESUMEN

Microglia, the brain resident macrophages, are first responders to any violation of central nervous system (CNS) homeostasis. A recent paper in Cell shows that the specific depletion of microglia causes deficits in learning-induced synaptic remodeling through paucity of the microglial neurotrophin brain-derived neurotrophic factor (BDNF).


Asunto(s)
Encéfalo/citología , Encéfalo/fisiología , Microglía/citología , Microglía/fisiología , Animales , Humanos
20.
Brain Behav Immun ; 55: 126-137, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26576722

RESUMEN

Microglia are suggested to be involved in several neuropsychiatric diseases. Indeed changes in microglia morphology have been reported in different mouse models of depression. A crucial regulatory system for microglia function is the well-defined CX3C axis. Thus, we aimed to clarify the role of microglia and CX3CR1 in depressive behavior by subjecting CX3CR1-deficient mice to a particular chronic despair model (CDM) paradigm known to exhibit face validity to major depressive disorder. In wild-type mice we observed the development of chronic depressive-like behavior after 5days of repetitive swim stress. 3D-reconstructions of Iba-1-labeled microglia in the dentate molecular layer revealed that behavioral effects were associated with changes in microglia morphology towards a state of hyper-ramification. Chronic treatment with the anti-depressant venlafaxine ameliorated depression-like behavior and restored microglia morphology. In contrast, CX3CR1 deficient mice showed a clear resistance to either (i) stress-induced depressive-like behavior, (ii) changes in microglia morphology and (iii) antidepressant treatment. Our data point towards a role of hyper-ramified microglia in the etiology of chronic depression. The lack of effects in CX3CR1 deficient mice suggests that microglia hyper-ramification is controlled by neuron-microglia signaling via the CX3C axis. However, it remains to be elucidated how hyper-ramified microglia contribute to depressive-like behavior.


Asunto(s)
Conducta Animal/fisiología , Quimiocina CX3CL1/deficiencia , Trastorno Depresivo Mayor/fisiopatología , Microglía/patología , Estrés Psicológico/complicaciones , Animales , Trastorno Depresivo Mayor/etiología , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA