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1.
Elife ; 122023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36594818

RESUMO

Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one-week post-injury. Then, using bulk RNA-seq, we assessed the differential long-term outcomes between young and aged mice following TBI. In our scRNA-seq studies, we highlight injury-related changes in differential gene expression seen in major meningeal cell populations including macrophages, fibroblasts, and adaptive immune cells. We found that TBI leads to an upregulation of type I interferon (IFN) signature genes in macrophages and a controlled upregulation of inflammatory-related genes in the fibroblast and adaptive immune cell populations. For reasons that remain poorly understood, even mild injuries in the elderly can lead to cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges 1.5 months after TBI. Notably, we found that aging alone induced upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited upregulation of immune-related genes and downregulation of genes involved in extracellular matrix remodeling. Overall, these findings illustrate the dynamic transcriptional response of the meninges to mild head trauma in youth and aging.


Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Lesões Encefálicas , Camundongos , Animais , Lesões Encefálicas Traumáticas/metabolismo , Concussão Encefálica/metabolismo , Concussão Encefálica/patologia , Lesões Encefálicas/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Meninges/patologia , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças
2.
Theranostics ; 13(1): 106-124, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593948

RESUMO

Rationale: The accumulation and clearance of amyloid-ß (Aß) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). The (re)discovery of meningeal lymphatic vessels in recent years has focused attention on the lymphatic clearance of Aß and has become a promising therapeutic target for such diseases. However, there is a lack of small molecular compounds that could clearly regulate meningeal lymphatic drainage to remove Aß from the brain. Methods: We investigated the effect of borneol on meningeal lymphatic clearance of macromolecules with different molecular weights (including Aß) in the brain. To further investigate the mechanism of borneol regulating meningeal lymphatic drainage, immunofluorescence staining, western blotting, ELISA, RT-qPCR, and Nitric Oxide assay kits were used. The cognitive function of AD mice after borneol treatment was evaluated using two behavioral tests: open field (OF) and Morris water maze (MWM). Results: This study discovered that borneol could accelerate the lymphatic clearance of Aß from the brain by enhancing meningeal lymphatic drainage. Preliminary mechanism analysis revealed that borneol could improve the permeability and inner diameter of lymphatic vessels, allowing macromolecules to drain into the cervical lymph nodes (CLNS) and then be transported to the lymphatic circulation. To speed up the clearance of macromolecules, borneol also stimulated lymphatic constriction by lowering the level of nitric oxide in the meninges. In addition, borneol stimulated lymphangiogenesis by increasing the levels of FOXC2, VEGFC, and LYVE-1 in the meninges, which promoted the clearance rates of macromolecules. Borneol improved meningeal lymphatic clearance not only for Aß but also for other macromolecular polymers (molecular weight in the range of 2 KD - 45 KD. Borneol ameliorated cognitive deficits and alleviated brain Aß burden in Aß-injected mice. Conclusions: Our findings not only provide a strategy to regulate lymphatic clearance pathways of macromolecules in the brain, but also new targets and ideas for treating neurodegenerative diseases like AD. Furthermore, our findings indicate that borneol is a promising therapeutic drug for AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/patologia , Óxido Nítrico/metabolismo , Encéfalo/metabolismo , Meninges/metabolismo , Meninges/patologia , Camundongos Transgênicos
3.
Elife ; 112022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36541708

RESUMO

The discovery of meningeal lymphatic vessels that drain the CNS has prompted new insights into how immune responses develop in the brain. In this study, we examined how T cell responses against CNS-derived antigen develop in the context of infection. We found that meningeal lymphatic drainage promotes CD4+ and CD8+ T cell responses against the neurotropic parasite Toxoplasma gondii in mice, and we observed changes in the dendritic cell compartment of the dural meninges that may support this process. Indeed, we found that mice chronically, but not acutely, infected with T. gondii exhibited a significant expansion and activation of type 1 and type 2 conventional dendritic cells (cDC) in the dural meninges. cDC1s and cDC2s were both capable of sampling cerebrospinal fluid (CSF)-derived protein and were found to harbor processed CSF-derived protein in the draining deep cervical lymph nodes. Disrupting meningeal lymphatic drainage via ligation surgery led to a reduction in CD103+ cDC1 and cDC2 number in the deep cervical lymph nodes and caused an impairment in cDC1 and cDC2 maturation. Concomitantly, lymphatic vessel ligation impaired CD4+ and CD8+ T cell activation, proliferation, and IFN-γ production at this site. Surprisingly, however, parasite-specific T cell responses in the brain remained intact following ligation, which may be due to concurrent activation of T cells at non-CNS-draining sites during chronic infection. Collectively, our work reveals that CNS lymphatic drainage supports the development of peripheral T cell responses against T. gondii but remains dispensable for immune protection of the brain.


Assuntos
Toxoplasma , Camundongos , Animais , Encéfalo/metabolismo , Meninges/patologia , Linfócitos T CD8-Positivos , Controle de Doenças Transmissíveis
5.
Nature ; 611(7936): 585-593, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36352225

RESUMO

Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer's disease (AD) and from non-AD individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD.


Assuntos
Sistema Nervoso Central , Líquido Cefalorraquidiano , Macrófagos , Tecido Parenquimatoso , Animais , Camundongos , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Líquido Cefalorraquidiano/metabolismo , Macrófagos/fisiologia , Meninges/citologia , Reologia , Proteínas da Matriz Extracelular/metabolismo , Envelhecimento/metabolismo , Fagocitose , Endocitose , Interferon gama/metabolismo , Tecido Parenquimatoso/citologia , Humanos
6.
Clin Transl Med ; 12(11): e1096, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36336786

RESUMO

The central nervous system (CNS) hosts a variety of immune cells, including two distinct macrophage populations: microglia are found in the parenchyma, whereas CNS-associated macrophages (CAMs) cover the CNS interfaces, such as the perivascular spaces, the meninges and the choroid plexus. Recent studies have given novel insights into the nature of CAMs as compared to microglia. In this mini-review, we summarise the current knowledge about the ontogenetic relationship and the underlying mechanism for the establishment of CNS macrophages during development.


Assuntos
Sistema Nervoso Central , Macrófagos , Microglia/fisiologia , Meninges , Plexo Corióideo
7.
Neurocirugia (Astur : Engl Ed) ; 33(6): 371-376, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36333095

RESUMO

Solitary fibrous tumors (SFTs) are neoplasms that grow from mesenchymal fusiform cells. In the central nervous system, meninges are the common origin of these neoplasms. Although literature reports mostly SFT as benign neoplasm, malignancy data have been described in recurrences or metastatic lesions. Definitive diagnosis includes immunohistochemical profiles assessing cellular positivity for CD34, vimentin, CD99 and Bcl-2. Recent studies have demonstrated NAB2-STAT6 gene fusion as a distinct molecular feature of SFT with overexpression of the fusion protein NAB2-STAT6 in nuclei of these cells. Since several years, pathologists have grouped SFT and hemangiopericytomas (HPC) as different phenotypes of the same entity although both neoplasms do not share numerous features. This article, based on a case of a recurrent malignant SFT, aims to emphasize differences in the SFT/HPC spectrum due to the diagnostic, therapeutic and prognostic implications.


Assuntos
Hemangiopericitoma , Neoplasias Meníngeas , Tumores Fibrosos Solitários , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Hemangiopericitoma/diagnóstico , Tumores Fibrosos Solitários/diagnóstico por imagem , Tumores Fibrosos Solitários/química , Meninges/patologia
8.
Cell Rep ; 41(7): 111648, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384109

RESUMO

The trigeminal sensory innervation of the cranial meninges is thought to serve a nociceptive function and mediate headache pain. However, the activity of meningeal afferents under natural conditions in awake animals remains unexplored. Here, we used two- and three-dimensional two-photon calcium imaging to track the activity of meningeal afferent fibers in awake mice. Surprisingly, a large subset of afferents was activated during non-noxious conditions such as locomotion. We estimated locomotion-related meningeal deformations and found afferents with distinct dynamics and tuning to various levels of meningeal expansion, compression, shearing, and Z-axis motion. Further, these mechanosensitive afferents were often tuned to distinct directions of meningeal expansion or compression. Thus, in addition to their role in headache-related pain, meningeal sensory neurons track the dynamic mechanical state of the meninges under natural conditions.


Assuntos
Meninges , Neurônios Aferentes , Animais , Camundongos , Neurônios Aferentes/fisiologia , Cefaleia , Locomoção
9.
J Cancer Res Ther ; 18(6): 1823-1826, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412455

RESUMO

Parameningeal rhabdomyosarcomas (PM RMSs) are rarely seen childhood tumors. Their treatment might be challenging and prognosis is poor compared to other head and neck RMS. Here we report a PM RMS presenting with leptomeningeal seeding metastasis a year after diagnosis. A five-year-old girl presented with an enlarging mass protruding from the right ear and right facial paralysis. Magnetic resonance imaging (MRI) revealed a large mass extending from right external auditory canal to the temporal lobe, pterygoid fossa and nasopharynx with an intracranial component indenting the right temporal lobe and extending into the right cavernous sinus. Trucut biopsy revealed embryonal rhabdomyosarcoma. Cerebrospinal fluid (CSF) cytology was negative for malignant cells. Chemotherapy was started since it was found unresectable. At second week of chemotherapy, radiotherapy was applied to primary tumor location with intensity-modulated radiation therapy (IMRT) technique in 1.8 Gy fractions to total dose of 50.4 Gy. At week 27, MRI showed significant response. At week 36, the patient presented with vomiting and tendency to sleep. MRI was found to be compatible with meningitis and antibacterial therapy was started. At week 39, chemotherapy was stopped. But MRI performed one month later revealed linear contrast enhancements around the spinal cord compatible with leptomeningeal metastases. Chemotherapy and craniospinal irradiation were applied. But the patient did not improve and received palliative treatment. Six months after the completion of radiotherapy the patient died. Treatment of parameningeal rhabdomyosarcomas require multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Prognosis is poor for patients with leptomeningeal spread.


Assuntos
Carcinomatose Meníngea , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Feminino , Humanos , Criança , Pré-Escolar , Rabdomiossarcoma/terapia , Meninges , Imageamento por Ressonância Magnética
10.
Immunity ; 55(11): 1969-1971, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351369

RESUMO

Border-associated macrophages (BAMs) reside at the interface between the brain and the periphery, including the meninges and choroid plexus. In this issue of Immunity, two studies report the dynamics, diversity, and fate of murine BAMs during infection, assigning these cells a neuroprotective role.


Assuntos
Macrófagos , Meninges , Animais , Camundongos , Plexo Corióideo , Encéfalo
11.
Cell Rep ; 41(6): 111592, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351383

RESUMO

Steady-state extramedullary hematopoiesis during adulthood is an emerging field of great interest. The meninges contain both innate and adaptive immune cells, which provide immunosurveillance of the central nervous system (CNS). Hematopoietic progenitors that give rise to meningeal immune cells remain elusive. Here, we report that steady-state meninges of adult mice host hematopoietic stem cells (HSCs), as defined by long-term, efficient, multi-lineage reconstitution and self-renewal capacity in the meninges, blood, spleen, and bone marrow of sublethally irradiated adult recipients. HSCs lodge in the meninges after birth with local expression of pro-hematopoietic niche factors. Meningeal HSCs are locally maintained in homeostasis and get replenished from the blood only when the resident pool is reduced. With a tissue-specific expression profile, meningeal HSCs can provide the CNS with a constant supply of leukocytes more adapted to local microenvironment.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Camundongos , Animais , Células-Tronco Hematopoéticas/metabolismo , Hematopoese/fisiologia , Medula Óssea , Baço , Meninges , Camundongos Endogâmicos C57BL
12.
Immunity ; 55(11): 2103-2117.e10, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36323311

RESUMO

The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II- MM were abundant neonatally, whereas MHC-II+ MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II+ MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation.


Assuntos
COVID-19 , Coriomeningite Linfocítica , Animais , Camundongos , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , SARS-CoV-2 , Vírus da Coriomeningite Linfocítica/fisiologia , Macrófagos , Meninges
13.
Neuron ; 110(21): 3418-3420, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36327892

RESUMO

In an interview with Neuron, Jony Kipnis discusses his formative academic years and subsequent discoveries in meningeal lymphatics. He is enthusiastic about the prospect of therapeutic developments in neuroimmunology arising from focusing on the brain's borders.


Assuntos
Sistema Linfático , Meninges , Humanos , Masculino
16.
Microbiol Spectr ; 10(5): e0250822, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36173332

RESUMO

HIV-1 sequence population structure among brain and nonbrain cellular compartments is incompletely understood. Here, we compared proviral pol and env high-quality consensus single-molecule real-time (SMRT) sequences derived from CD3+ T cells and CD14+ macrophage lineage cells from meningeal or peripheral (spleen, blood) tissues obtained at autopsy from two individuals with viral suppression on antiretroviral therapy (ART). Phylogenetic analyses showed strong evidence of population structure between CD3+ and CD14+ virus populations. Distinct env variable-region characteristics were also found between CD3+ and CD14+ viruses. Furthermore, shared macrophage-tropic amino acid residues (env) and drug resistance mutations (pol) between meningeal and peripheral virus populations were consistent with the meninges playing a role in viral gene flow across the blood-brain barrier. Overall, our results point toward potential functional differences among meningeal and peripheral CD3+ and CD14+ virus populations and a complex evolutionary history driven by distinct selection pressures and/or viral gene flow. IMPORTANCE Different cell types and/or tissues may serve as a reservoir for HIV-1 during ART-induced viral suppression. We compared proviral pol and env sequences from CD3+ T cells and CD14+ macrophage lineage cells from brain and nonbrain tissues from two virally suppressed individuals. We found strong evidence of viral population structure among cells/tissues, which may result from distinct selective pressures across cell types and anatomic sites.


Assuntos
Infecções por HIV , HIV-1 , Humanos , HIV-1/genética , Filogenia , Linfócitos T , Infecções por HIV/tratamento farmacológico , Macrófagos , Meninges , Aminoácidos
17.
Psychiatr Danub ; 34(Suppl 8): 265-275, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36170741

RESUMO

Medical psychiatry acquires more prominence in the biological field by new anatomical insights into the wrappings of the brain: meninges, but also Meningo-Calvarial Channels (MCCs) connecting the former with the bone marrows' also neuronally steered, functions. The skull-bone's meningeal arteries through migrating and orchestrating mast cells within a framework stressing their relations with arteries (Treviranus 2012-21) could explain enigmatic phenomena like migrainous and post-injury Cortical Spreading Depressions (CSD) or the Reversible Cerebral Vasoconstriction Syndrome (RCVS) escalating to "PRES". The skull might be accessed along chronic (para-)infectious paths resulting in Skull Bone Osteomyelitis (SBO) from the ear-nose-throat, dental and other microbiomes. Such paths seem promoted by compromised innate immune defenses: by "Mendelian" susceptibility, and/or acquired anti-INF-γ- or other auto-immunity or various microbial "Trojans" of e. g. meningeal myelo- and lymphocytes. These interact e. g. from the calvarial marrow niches onward. Hereby competing local and "intentional" intruding mast cells - by disturbing (or ingeniously boosting) cortical development and functioning - acquire relevance by interacting with arteries (Treviranus 2018, 2021). This predicts findings in behavior (Fitzpatrick & Morrow 2017) an "aortal" arterial biomechanical foundation of parasympathetic reverse arterio-intramural cerebro-interstitial drainage by CIMURAF/IPAD-2.0 (Treviranus 2018-21). Here the recent physiological re-conceptions of the skull illuminate own case histories through a gamut of possibly relevant neuro(-surgico)-psychiatric challenges. Among these meningo-cerebral immune, vasospastic, and cystic processes some generate broad "experiential" hallucinations, which may slowly transit to true psychoses through "perfect crime lesions" of neurons and glia by tryptase-armed mast cells descending into parenchyma often congested by "push-back". These emerging hypotheses coalesce in advancing an integrative macro-medical psychiatry and even the pathography of Van Gogh and Mozart stressing the benign and creative roles of mast cells.


Assuntos
Mastócitos , Meninges , Cabeça , Humanos , Crânio , Triptases
18.
Immunol Rev ; 311(1): 9-25, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35984321

RESUMO

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 , Neuroimunomodulação
20.
Nat Commun ; 13(1): 4825, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974004

RESUMO

Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.


Assuntos
Transtorno Depressivo Maior , Vasos Linfáticos , Animais , Feminino , Sistema Linfático , Vasos Linfáticos/fisiologia , Masculino , Meninges , Camundongos , Caracteres Sexuais , Estresse Psicológico
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