RESUMO
Human T cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and the demyelinating neuroinflammatory disease known as HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), was the first human retrovirus to be discovered. T-cells, which represent the main reservoir for HTLV-1, have been the main focus of studies aimed at understanding viral transmission and disease progression. However, other cell types such as myeloid cells are also target of HTLV-1 infection and display functional alterations as a consequence. In this work, we review the current investigations that shed light on infection, transmission and functional alterations subsequent to HTLV-1 infection of the different myeloid cells types, and we highlight the lack of knowledge in this regard.
Assuntos
Infecções por HTLV-I/transmissão , Infecções por HTLV-I/virologia , Células Mieloides/imunologia , Células Mieloides/virologia , Animais , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/virologia , Macrófagos/imunologia , Macrófagos/virologia , Linfócitos T/imunologia , Linfócitos T/virologiaRESUMO
PRIMARY OBJECTIVE: The aim of this study was to investigate the reparative potential of a polymeric scaffold designed for brain tissue repair in combination with lipoic acid. RESEARCH DESIGN: Histological, cytological and structural analysis of a combined treatment after a brain cryo-injury model in rats. METHODS AND PROCEDURES: Adult Wistar rats were subjected to cryogenic brain injury. A channelled-porous scaffold of ethyl acrylate and hydroxyethylacrylate, p(EA-co-HEA) was grafted into cerebral penumbra alone or combined with intraperitoneal LA administration. Histological and cytological evaluation was performed after 15 and 60 days and structural magnetic resonance (MRI) assessment was performed at 2 and 6 months after the surgery. MAIN OUTCOMES AND RESULTS: The scaffold was suitable for the establishment of different cellular types. The results obtained suggest that this strategy promotes blood vessels formation, decreased microglial response and neuron migration, particularly when LA was administrated. CONCLUSIONS: These evidences demonstrated that the combination of a channelled polymer scaffold with LA administration may represent a potential treatment for neural tissue repair after brain injury.
Assuntos
Acrilatos/uso terapêutico , Amilopectina/análogos & derivados , Lesões Encefálicas Traumáticas/terapia , Ácido Tióctico/uso terapêutico , Amilopectina/uso terapêutico , Animais , Encéfalo/patologia , Lesões Encefálicas/reabilitação , Lesões Encefálicas/terapia , Masculino , Plásticos , Ratos , Ratos Wistar , Alicerces TeciduaisRESUMO
Ochratoxin A (OTA), a mycotoxin that was discovered as a secondary metabolite of the fungal species Aspergillus and Penicillium, is a common contaminant in food and animal feed. This mycotoxin has been described as teratogenic, carcinogenic, genotoxic, immunotoxic and has been proven a potent neurotoxin. Other authors have previously reported the effects of OTA in different structures of the central nervous system as well as in some neurogenic regions. However, the impact of OTA exposure in the subventricular zone (SVZ) has not been assessed yet. To elucidate whether OTA affects neural precursors of the mouse SVZ we investigated, in vitro and in vivo, the effects of OTA exposure on the SVZ and on the neural precursors obtained from this neurogenic niche. In this work, we prove the cumulative effect of OTA exposure on proliferation, differentiation and depletion of neural stem cells cultured from the SVZ. In addition, we corroborated these results in vivo by immunohistochemistry and electron microscopy. As a result, we found a significant alteration in the proliferation process, which was evidenced by a decrease in the number of 5-bromo-2-deoxyuridine-positive cells and glial cells, as well as, a significant decrease in the number of neuroblasts in the SVZ. To summarize, in this study we demonstrate how OTA could be a threat to the developing and the adult SVZ through its impact in cell viability, proliferation and differentiation in a dose-dependent manner.
Assuntos
Ventrículos Laterais/efeitos dos fármacos , Micotoxinas/toxicidade , Ocratoxinas/toxicidade , Animais , Astrócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ventrículos Laterais/patologia , Ventrículos Laterais/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Células-Tronco Neurais/efeitos dos fármacos , Neuroglia/efeitos dos fármacosRESUMO
After trauma brain injury, oxidative substances released to the medium provoke an enlargement of the initial lesion, increasing glial cell activation and, occasionally, an influx of immune cells into the central nervous system, developing the secondary damage. In response to these stimuli, microglia are activated to perform upregulation of intracellular enzymes and cell surface markers to propagate the immune response and phagocytosis of cellular debris. The phagocytosis of debris and dead cells is essential to limit the inflammatory reaction and potentially prevent extension of the damage to noninjured regions. Lipoic acid has been reported as a neuroprotectant by acting as an antioxidant and anti-inflammatory agent. Furthermore, angiogenic effect promoted by lipoic acid has been recently shown by our group as a crucial process for neural regeneration after brain injury. In this work, we focus our attention on the lipoic acid effect on astroglial and microglial response after brain injury.
Assuntos
Antioxidantes/farmacologia , Astrócitos/imunologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/imunologia , Microglia/imunologia , Fármacos Neuroprotetores/farmacologia , Ácido Tióctico/farmacologia , Animais , Antioxidantes/administração & dosagem , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/patologia , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ácido Tióctico/administração & dosagemRESUMO
There is increasing evidence that viral infections are the source/origin of various types of encephalitis, encephalomyelitis, and other neurological and cognitive disorders. While the involvement of certain viruses, such as the Nipah virus and measles virus, is known, the mechanisms of neural invasion and the factors that trigger intense immune reactions are not fully understood. Based on recent publications, this review discusses the role of the immune response, interactions between viruses and glial cells, and cytokine mediators in the development of inflammatory diseases in the central nervous system. It also highlights the significant gaps in knowledge regarding these mechanisms.
RESUMO
The human T-cell leukemia virus (HTLV)-1 is responsible for an aggressive neurodegenerative disease (HAM/TSP) and multiple neurological alterations. The capacity of HTLV-1 to infect central nervous system (CNS) resident cells, together with the neuroimmune-driven response, has not been well-established. Here, we combined the use of human induced pluripotent stem cells (hiPSC) and of naturally STLV-1-infected nonhuman primates (NHP) as models with which to investigate HTLV-1 neurotropism. Hence, neuronal cells obtained after hiPSC differentiation in neural polycultures were the main cell population infected by HTLV-1. Further, we report the infection of neurons with STLV-1 in spinal cord regions as well as in brain cortical and cerebellar sections of postmortem NHP. Additionally, reactive microglial cells were found in infected areas, suggesting an immune antiviral response. These results emphasize the need to develop new efficient models by which to understand HTLV-1 neuroinfection and suggest an alternative mechanism that leads to HAM/TSP.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Vírus Linfotrópico T Tipo 1 de Símios , Animais , Humanos , Encéfalo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Primatas , NeurôniosRESUMO
Ependymal cells are radial glia-derived multiciliated cells lining the lateral ventricles of the brain and spinal cord. Correct development and coordinated cilia beating is essential for proper cerebrospinal fluid (CSF) flow and neurogenesis modulation. Dysfunctions of ependymal cells were associated with transcription factor deregulation. Here we provide evidence that the transcriptional regulator ID4 is involved in ependymal cell development and maturation. We observed that Id4-deficient mice display altered ventricular cell cytoarchitecture, decreased ependymal cell number and enlarged ventricles. In addition, absence of ID4 during embryonic development resulted in decreased ependymal cell number and delayed maturation. Our findings open the way for a potential role of ID4 in ependymal cell development and motor cilia function.
RESUMO
The Human T-cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a devastating neurodegenerative disease with no effective treatment, which affects an increasing number of people in Brazil. Immune cells from the adaptive compartment are involved in disease manifestation but whether innate cell functions participate in disease occurrence has not been evaluated. In this study, we analyzed innate cell responses at steady state and after blood cell stimulation using an agonist of the toll-like receptor (TLR)7/8-signaling pathway in blood samples from HTLV-1-infected volunteers, including asymptomatic carriers and HAM/TSP patients. We observed a lower response of IFNα+ DCs and monocytes in HAM/TSP compared to asymptomatic carriers, as a potential consequence of corticosteroid treatments. In contrast, a higher frequency of monocytes producing MIP-1α and pDC producing IL-12 was detected in HAM/TSP blood samples, together with higher IFNγ responsiveness of NK cells, suggesting an increased sensitivity to inflammatory response in HAM/TSP patients compared to asymptomatic carriers. This sustained inflammatory responsiveness could be linked or be at the origin of the neuroinflammatory status in HAM/TSP patients. Therefore, the mechanism underlying this dysregulations could shed light onto the origins of HAM/TSP disease.
Assuntos
Imunidade Inata , Paraparesia Espástica Tropical/imunologia , Adulto , Brasil , Estudos de Coortes , Células Dendríticas/imunologia , Feminino , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Paraparesia Espástica Tropical/virologiaRESUMO
Quiescence is essential for the long-term maintenance of adult stem cells but how stem cells maintain quiescence is poorly understood. Here, we show that neural stem cells (NSCs) in the adult mouse hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activated or quiescent states. We found that the inhibitor of DNA binding protein Id4 is enriched in quiescent NSCs and that elimination of Id4 results in abnormal accumulation of Ascl1 protein and premature stem cell activation. Accordingly, Id4 and other Id proteins promote elimination of Ascl1 protein in NSC cultures. Id4 sequesters Ascl1 heterodimerization partner E47, promoting Ascl1 protein degradation and stem cell quiescence. Our results highlight the importance of non-transcriptional mechanisms for the maintenance of NSC quiescence and reveal a role for Id4 as a quiescence-inducing factor, in contrast with its role of promoting the proliferation of embryonic neural progenitors.
Assuntos
Células-Tronco Adultas/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células , Hipocampo/citologia , Proteínas Inibidoras de Diferenciação/metabolismo , Células-Tronco Neurais/fisiologia , Animais , Células Cultivadas , Camundongos , Ligação Proteica , Fator 3 de Transcrição/metabolismoRESUMO
Anamniotes, rodents, and young humans maintain neural stem cells in the ependymal zone (EZ) around the central canal of the spinal cord, representing a possible endogenous source for repair in mammalian lesions. Cell diversity and genes specific for this region are ill defined. A cellular and molecular resource is provided here for the mouse and human EZ based on RNA profiling, immunostaining, and fluorescent transgenic mice. This uncovered the conserved expression of 1,200 genes including 120 transcription factors. Unexpectedly the EZ maintains an embryonic-like dorsal-ventral pattern of expression of spinal cord developmental transcription factors (ARX, FOXA2, MSX1, and PAX6). In mice, dorsal and ventral EZ cells express Vegfr3 and are derived from the embryonic roof and floor plates. The dorsal EZ expresses a high level of Bmp6 and Gdf10 genes and harbors a subpopulation of radial quiescent cells expressing MSX1 and ID4 transcription factors.