RESUMO
The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier.
RESUMO
Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate tracing and intracranial mast-cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross the blood-brain barrier, inhibit TAH in vivo, and alleviate mast-cell-induced damage of epithelial cilia in a human pluripotent stem-cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.
Assuntos
Neoplasias Encefálicas , Plexo Corióideo , Hidrocefalia , Mastócitos , Humanos , Neoplasias Encefálicas/secundário , Plexo Corióideo/metabolismo , Plexo Corióideo/patologia , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Triptases/líquido cefalorraquidiano , Metástase Neoplásica/patologiaRESUMO
The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.
Assuntos
Plexo Corióideo , Hidrocefalia , Humanos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Plexo Corióideo/metabolismo , Hidrocefalia/líquido cefalorraquidiano , Hidrocefalia/imunologia , Imunidade Inata , Síndrome da Liberação de Citocina/patologiaRESUMO
The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas of each ChP in the developing, adult, and aged mouse brain. We delineate diverse cell types, subtypes, cell states, and expression programs in epithelial and mesenchymal cells across ages and ventricles. In the developing ChP, we predict a common progenitor pool for epithelial and neuronal cells, validated by lineage tracing. Epithelial and fibroblast cells show regionalized expression by ventricle, starting at embryonic stages and persisting with age, with a dramatic transcriptional shift with maturation, and a smaller shift in each aged cell type. With aging, epithelial cells upregulate host-defense programs, and resident macrophages upregulate interleukin-1ß (IL-1ß) signaling genes. Our atlas reveals cellular diversity, architecture and signaling across ventricles during development, maturation, and aging of the ChP-brain barrier.
Assuntos
Plexo Corióideo/embriologia , Plexo Corióideo/metabolismo , Fatores Etários , Envelhecimento/fisiologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Encefalopatias/genética , Encefalopatias/fisiopatologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Plexo Corióideo/fisiologia , Células Epiteliais/metabolismo , Feminino , Masculino , Camundongos/embriologia , Camundongos Endogâmicos C57BL , Transdução de Sinais , Análise de Célula ÚnicaRESUMO
We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course. C3 expression in primary tumors was predictive of leptomeningeal relapse. Mechanistically, we found that cancer-cell-derived C3 activates the C3a receptor in the choroid plexus epithelium to disrupt the blood-CSF barrier. This effect allows plasma components, including amphiregulin, and other mitogens to enter the CSF and promote cancer cell growth. Pharmacologic interference with C3 signaling proved therapeutically beneficial in suppressing leptomeningeal metastasis in these preclinical models.
Assuntos
Complemento C3/metabolismo , Neoplasias Meníngeas/secundário , Metástase Neoplásica/patologia , Animais , Neoplasias da Mama/patologia , Líquido Cefalorraquidiano , Plexo Corióideo/irrigação sanguínea , Complemento C3/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pulmonares/patologia , Antígeno de Macrófago 1/metabolismo , Camundongos , Transdução de Sinais , Microambiente Tumoral , Regulação para CimaRESUMO
Studies of the choroid plexus lag behind those of the more widely known blood-brain barrier, despite a much longer history. This review has two overall aims. The first is to outline long-standing areas of research where there are unanswered questions, such as control of cerebrospinal fluid (CSF) secretion and blood flow. The second aim is to review research over the past 10 years where the focus has shifted to the idea that there are choroid plexuses located in each of the brain's ventricles that make specific contributions to brain development and function through molecules they generate for delivery via the CSF. These factors appear to be particularly important for aspects of normal brain growth. Most research carried out during the twentieth century dealt with the choroid plexus, a brain barrier interface making critical contributions to the composition and stability of the brain's internal environment throughout life. More recent research in the twenty-first century has shown the importance of choroid plexus-generated CSF in neurogenesis, influence of sex and other hormones on choroid plexus function, and choroid plexus involvement in circadian rhythms and sleep. The advancement of technologies to facilitate delivery of brain-specific therapies via the CSF to treat neurological disorders is a rapidly growing area of research. Conversely, understanding the basic mechanisms and implications of how maternal drug exposure during pregnancy impacts the developing brain represents another key area of research.
Assuntos
Barreira Hematoencefálica , Plexo Corióideo , Humanos , Barreira Hematoencefálica/fisiologia , Encéfalo , Transporte Biológico/fisiologia , Ventrículos CerebraisRESUMO
The brain's neuroreparative capacity after injuries such as ischemic stroke is partly contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here, we report a mouse genetic tool (the ROSA26iDTR mouse line) for noninvasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss in both aged and young adult brains, accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at 1 mo postablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts (NBs) following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the middle cerebral artery occlusion model of ischemic stroke, NB migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke.
Assuntos
Plexo Corióideo , Ventrículos Laterais , Neurogênese , Animais , Plexo Corióideo/metabolismo , Neurogênese/fisiologia , Camundongos , Ventrículos Laterais/metabolismo , Ventrículos Laterais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Masculino , Movimento Celular , Ventrículos Cerebrais/metabolismoRESUMO
The brain is a complex organ, fundamentally changing across the day to perform basic functions like sleep, thought, and regulating whole-body physiology. This requires a complex symphony of nutrients, hormones, ions, neurotransmitters and more to be properly distributed across the brain to maintain homeostasis throughout 24 hours. These solutes are distributed both by the blood and by cerebrospinal fluid. Cerebrospinal fluid contents are distinct from the general circulation because of regulation at brain barriers including the choroid plexus, glymphatic system, and blood-brain barrier. In this review, we discuss the overlapping circadian (≈24-hour) rhythms in brain fluid biology and at the brain barriers. Our goal is for the reader to gain both a fundamental understanding of brain barriers alongside an understanding of the interactions between these fluids and the circadian timing system. Ultimately, this review will provide new insight into how alterations in these finely tuned clocks may lead to pathology.
Assuntos
Barreira Hematoencefálica , Encéfalo , Barreira Hematoencefálica/fisiologia , Homeostase/fisiologia , Ritmo Circadiano , BiologiaRESUMO
Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here, we used high-throughput single-nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in six extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases-for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the data presented here complete a "Version 1" cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as the neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.
Assuntos
Glaucoma , Disco Óptico , Humanos , Transcriptoma , Células Endoteliais , Glaucoma/genética , Nervo Óptico , EscleraRESUMO
The central nervous system (CNS) has been viewed as an immunologically privileged site, but emerging works are uncovering a large array of neuroimmune interactions primarily occurring at its borders. CNS barriers sites host diverse population of both innate and adaptive immune cells capable of, directly and indirectly, influence the function of the residing cells of the brain parenchyma. These structures are only starting to reveal their role in controlling brain function under normal and pathological conditions and represent an underexplored therapeutic target for the treatment of brain disorders. This review will highlight the development of the CNS barriers to host neuro-immune interactions and emphasize their newly described roles in neurodevelopmental, neurological, and neurodegenerative disorders, particularly for the meninges.
Assuntos
Encéfalo , Doenças Neurodegenerativas , Sistema Nervoso Central , Humanos , Meninges , NeuroimunomodulaçãoRESUMO
Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the developed world. Vision loss in the advanced stages of the disease is caused by atrophy of retinal photoreceptors, overlying retinal pigment epithelium (RPE) and choroidal endothelial cells. The molecular events that underline the development of these cell types from in utero to adult as well as the progression to intermediate and advanced stages AMD are not yet fully understood. We performed single-cell RNA-sequencing (RNA-Seq) of human fetal and adult RPE-choroidal tissues, profiling in detail all the cell types and elucidating cell type-specific proliferation, differentiation and immunomodulation events that occur up to midgestation. Our data demonstrate that progression from the fetal to adult state is characterized by an increase in expression of genes involved in the oxidative stress response and detoxification from heavy metals, suggesting a better defence against oxidative stress in the adult RPE-choroid tissue. Single-cell comparative transcriptional analysis between a patient with intermediate AMD and an unaffected subject revealed a reduction in the number of RPE cells and melanocytes in the macular region of the AMD patient. Together these findings may suggest a macular loss of RPE cells and melanocytes in the AMD patients, but given the complex processing of tissues required for single-cell RNA-Seq that is prone to technical artefacts, these findings need to be validated by additional techniques in a larger number of AMD patients and controls.
Assuntos
Degeneração Macular , Epitélio Pigmentado da Retina , Humanos , Adulto , Epitélio Pigmentado da Retina/metabolismo , Células Endoteliais/metabolismo , Corioide/metabolismo , Degeneração Macular/genética , Degeneração Macular/metabolismo , Desenvolvimento Fetal , Análise de Sequência de RNARESUMO
Glymphatic dysfunction has been correlated with cognitive decline, with a higher choroid plexus volume (CPV) being linked to a slower glymphatic clearance rate. Nevertheless, the interplay between CPV, glymphatic function, and cognitive impairment in white matter hyperintensities (WMHs) has not yet been investigated. In this study, we performed neuropsychological assessment, T1-weighted three-dimensional (3D-T1) images, and diffusion tensor imaging (DTI) in a cohort of 206 WMHs subjects and 43 healthy controls (HCs) to further explore the relationship. The DTI analysis along the perivascular space (DTI-ALPS) index, as a measure of glymphatic function, was calculated based on DTI. Severe WMHs performed significantly worse in information processing speed (IPS) than other three groups, as well as in executive function than HCs and mild WMHs. Additionally, severe WMHs demonstrated lower DTI-ALPS index and higher CPV than HCs and mild WMHs. Moderate WMHs displayed higher CPV than HCs and mild WMHs. Mini-Mental State Examination, IPS, and executive function correlated negatively with CPV but positively with DTI-ALPS index in WMHs patients. Glymphatic function partially mediated the association between CPV and IPS, indicating a potential mechanism for WMHs-related cognitive impairment. CPV may act as a valuable prognostic marker and glymphatic system as a promising therapeutic target for WMHs-related cognitive impairment.
Assuntos
Plexo Corióideo , Disfunção Cognitiva , Imagem de Tensor de Difusão , Sistema Glinfático , Substância Branca , Humanos , Masculino , Feminino , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/patologia , Plexo Corióideo/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/patologia , Sistema Glinfático/fisiopatologia , Pessoa de Meia-Idade , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/patologia , Testes Neuropsicológicos , Imageamento por Ressonância Magnética/métodos , Velocidade de ProcessamentoRESUMO
The intricate relationship between the central nervous system (CNS) and the immune system plays a crucial role in the pathogenesis of various neurological diseases. Understanding the interactions among the immunopathological processes at the brain borders is essential for advancing our knowledge of disease mechanisms and developing novel diagnostic and therapeutic approaches. In this review, we explore the emerging role of neuroimaging in providing valuable insights into brain barrier inflammation and brain fluid drainage in human neurological diseases. Neuroimaging techniques have enabled us not only to visualize and assess brain structures, but also to study the dynamics of the CNS in health and disease in vivo. By analyzing imaging findings, we can gain a deeper understanding of the immunopathology observed at the brain-immune interface barriers, which serve as critical gatekeepers that regulate immune cell trafficking, cytokine release, and clearance of waste products from the brain. This review explores the integration of neuroimaging data with immunopathological findings, providing valuable insights into brain barrier integrity and immune responses in neurological diseases. Such integration may lead to the development of novel diagnostic markers and targeted therapeutic approaches that can benefit patients with neurological disorders.
Assuntos
Sistema Glinfático , Doenças do Sistema Nervoso , Humanos , Sistema Glinfático/patologia , Encéfalo/patologia , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/terapia , Doenças do Sistema Nervoso/patologia , Inflamação/diagnóstico por imagem , Inflamação/patologia , Barreira Hematoencefálica/diagnóstico por imagemRESUMO
The cerebrospinal fluid (CSF) fills the brain ventricles and the subarachnoid space surrounding the brain and spinal cord. The fluid compartment of the brain ventricles communicates with the interstitial fluid of the brain across the ependyma. In comparison to blood, the CSF contains very little protein to buffer acid-base challenges. Nevertheless, the CSF responds efficiently to changes in systemic pH by mechanisms that are dependent on the CO2/HCO3- buffer system. This is evident from early studies showing that the CSF secretion is sensitive to inhibitors of acid/base transporters and carbonic anhydrase. The CSF is primarily generated by the choroid plexus, which is a well-vascularized structure arising from the pial lining of the brain ventricles. The epithelial cells of the choroid plexus host a range of acid/base transporters, many of which participate in CSF secretion and most likely contribute to the transport of acid/base equivalents into the ventricles. This review describes the current understanding of the molecular mechanisms in choroid plexus acid/base regulation and the possible role in CSF pH regulation.
Assuntos
Encéfalo , Plexo Corióideo , Plexo Corióideo/metabolismo , Encéfalo/metabolismo , Transporte Biológico , Medula Espinal , Concentração de Íons de HidrogênioRESUMO
BACKGROUND: The dysregulation of the gut-brain axis in chronic inflammatory bowel diseases can cause neuro-psychological disturbances, but the underlying mechanisms are still not fully understood. The choroid plexus (CP) maintains brain homeostasis and nourishment through the secretion and clearance of cerebrospinal fluid. Recent research has demonstrated the existence of a CP vascular barrier in mice which is modulated during intestinal inflammation. This study investigates possible correlations between CP modifications and inflammatory activity in patients with Crohn's disease (CD). METHODS: In this prospective study, 17 patients with CD underwent concomitant abdominal and brain 3 T MRI. The volume and permeability of CP were compared with levels of C-reactive protein (CRP), fecal calprotectin (FC), sMARIA and SES-CD scores. RESULTS: The CP volume was negatively correlated with CRP levels (R = -0.643, p-value = 0.024) and FC (R = -0.571, p-value = 0.050). DCE metrics normalized by CP volume were positively correlated with CRP (K-trans: R = 0.587, p-value = 0.045; Vp: R = 0.706, p-value = 0.010; T1: R = 0.699, p-value = 0.011), and FC (Vp: R = 0.606, p-value = 0.037). CONCLUSIONS: Inflammatory activity in patients with CD is associated with changes in CP volume and permeability, thus supporting the hypothesis that intestinal inflammation could affect the brain through the modulation of CP vascular barrier also in humans.
Assuntos
Doença de Crohn , Humanos , Animais , Camundongos , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/metabolismo , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/metabolismo , Estudos Prospectivos , Eixo Encéfalo-Intestino , Biomarcadores/metabolismo , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Índice de Gravidade de Doença , Inflamação/diagnóstico por imagem , PermeabilidadeRESUMO
Posterior polar annular choroidal dystrophy (PPACD) is a rare ocular disorder and presents as symmetric degeneration of the retinal pigment epithelium (RPE) and the underlying choriocapillaris, encircling the retinal vascular arcades and optic disc. This condition distinctively preserves the foveal region, optic disc, and the outermost regions of the retina. Despite its distinct clinical presentation, due to the infrequency of its occurrence and the limited number of reported cases, the pathophysiology, and the genetic foundations of PPACD are still largely uncharted. This review aims to bridge this knowledge gap by investigating potential genetic contributors to PPACD, assessing current findings, and identifying genes that warrant further study. Emphasis is also placed on the crucial role of multimodal imaging in diagnosing PPACD, highlighting its importance in understanding disease pathophysiology. By analyzing existing case reports and drawing comparisons with similar retinal disorders, this paper endeavors to delineate the possible genetic correlations in PPACD, providing a foundation for future genetic research and the development of targeted diagnostic strategies.
RESUMO
PURPOSE: We studied changes in the choroid, particularly variation in blood flow, during the development of myopia. The hemodynamic mechanism in play remains unclear. We evaluated blood flow by quantitating indocyanine green (ICG) fluorescence in a guinea pig model of form-deprivation myopia. METHODS: Guinea pigs were divided into form-deprivation myopia (FDM) and normal control (NC) groups. Ocular biometric and choroidal hemodynamics parameters were quantitatively derived via ICG imaging, and included the maximal ICG fluorescence intensity (Imax), rising time (Trising), blood flow index (BFI), and mean transit time (MTT). RESULTS: Form deprivation was associated with significant interocular differences in terms of both refractive error and axial length. ICG fluorescence hemodynamic maps of fundal blood flow and vasculature density were evident. In deprived eyes, the fluorescence signals exhibited significantly longer Trising and MTT but lower Imax and BFI than fellow eyes and NC group. The interocular differences in terms of the ocular biometric and hemodynamic parameters were significantly correlated. Hemodynamic analysis of choriocapillaris lobules revealed weakened fluorescence intensity and prolonged arrival and filling times in deprived eyes. Form deprivation reduced the number of lobulated choriocapillaris structures. CONCLUSION: Form-deprivation myopia triggered changes in the hemodynamic and vascular network structures of the choroid and choriocapillaris. The ICG fluorescence imaging/analysis method provides a unique tool for further myopia research.
Assuntos
Miopia , Erros de Refração , Animais , Cobaias , Diagnóstico por Imagem , Corioide/diagnóstico por imagem , HemodinâmicaRESUMO
The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.
Assuntos
Plexo Corióideo/embriologia , Epitélio/metabolismo , Quarto Ventrículo/embriologia , Proteína Meis1/metabolismo , Proteína Wnt-5a/metabolismo , Animais , Encéfalo/embriologia , Sistemas CRISPR-Cas/genética , Linhagem Celular , Células Epiteliais/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Transdução de Sinais/fisiologia , Proteína Wnt-5a/genéticaRESUMO
The notion that the central nervous system is an immunologically immune-exempt organ has changed over the past two decades, with increasing evidence of strong links and interactions between the central nervous system and the peripheral immune system, both in the healthy state and after ischemic and hemorrhagic stroke. Although primary injury after stroke is certainly important, the limited therapeutic efficacy, poor neurological prognosis and high mortality have led researchers to realize that secondary injury and damage may also play important roles in influencing long-term neurological prognosis and mortality and that the neuroinflammatory process in secondary injury is one of the most important influences on disease progression. Here, we summarize the interactions of the central nervous system with the peripheral immune system after ischemic and hemorrhagic stroke, in particular, how the central nervous system activates and recruits peripheral immune components, and we review recent advances in corresponding therapeutic approaches and clinical studies, emphasizing the importance of the role of the peripheral immune system in ischemic and hemorrhagic stroke.
Assuntos
Lesões Encefálicas , Isquemia Encefálica , Neoplasias Encefálicas , Acidente Vascular Cerebral Hemorrágico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral Hemorrágico/complicações , Isquemia Encefálica/complicações , Encéfalo , Acidente Vascular Cerebral/complicações , Lesões Encefálicas/complicações , Neoplasias Encefálicas/complicaçõesRESUMO
The coronavirus disease of 2019 (COVID-19) pandemic has led to more than 700 million confirmed cases and nearly 7 million deaths. Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains an important question, which is also centered on the mystery of whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to neurological complications both acutely and in long COVID.