Meningeal natural killer cells and innate lymphoid cells 1 tune anxiety and memory via interferon-γ and acetylcholine
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212089 | GEO | 2023/05/05
REPOSITORIES: GEO
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Project description:Postnatal brain neurogenesis in mammals is believed to be restricted to rare germinative remnants of the neuroepithelium. In this study, we discovered that, in the postnatal brain, a subset of embryonically derived progenitors is present in meningeal substructures. These cells migrate from the meningeal substructures to the retrosplenial and visual motor cortex and differentiate into (electrically) functional integrated neurons. Lineage tracing analysis revealed that this subset of neural progenitors originate largely from PDGFR+ cells. PDGFR-derived cells differentiate mostly into Satb2+ neurons in cortical layers I-IV. Thus, a reservoir of embryonically derived progenitors in the meninges contributes to postnatal cerebral cortical neurogenesis.
2016-11-23 | E-MTAB-4951 | biostudies-arrayexpress
Project description:The meninges are a tripartite system of membranous tissue comprised of pial, arachnoid and dural layers that cover both the brain and spinal cord. Between the arachnoid and pial layers is the subarachnoid space filled with cerebrospinal fluid (CSF). Though the meninges have long been thought to provide largely a protective function, a growing number of studies highlight this tissue to be a nest of immune activity, harboring T cells, B cells, macrophages, and a variety of other myeloid cell types during health and disease. But despite the burgeoning prospect that the meninges might play a decidedly more active role in immune and other regulatory processes than previously thought, little is known about their structural makeup. Contributing to this void, considerable technical challenges prevent sophisticated analysis of the meninges at cellular and molecular levels. In addition, removal of the brain and spinal cord from their bony encasement leads to tearing of the tenuous meninges and significant disruption of the delicate inter-membrane arrangements. Also lacking are sufficient molecular targets to identify the various meningeal structural elements, only hinted at so far by scanning electron microscopy. Accordingly, we developed a method to allow removal of brain and spinal meninges while minimizing risk of parenchymal contamination and performed shotgun proteomics on the two meningeal domains. While the vast majority of proteins at both locales overlapped, several proteins – including those of structural nature – were exclusive to brain or spinal meninges. Targeting proteins revealed in the proteomic data, the cellular and extracellular elements that provide the meninges’ structure were identified using confocal and electron microscopy, and were observed for the first time in high-resolution
2023-11-01 | PXD039294 | Pride
Project description:By characterizing the meningeal compartment of naive mice, here we explored a unique population of tissue-resident gd T cells, which we found to be the major source of IL-17A in the steady state meninges. gd T cells rapidly harbor meninges at perinatal stages and actively make IL-17A. Their IL-17A production was TCR-dependent but it occurred independent of commensal microbiota. The absence of meningeal gd T cells was related with risk-taking behavior in mice, which was dependent on the IL-17A signaling directly in the prefrontal cortex neurons. Our results demonstrate that tissue-resident meningeal gd T cell-derived IL-17A may represent an evolutionary bridge between anti-pathogen response and avoidance behavioral traits in vertebrates.
2020-07-24 | GSE132047 | GEO
Project description:The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid and pial. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial sub-population marked by expression of µ-Crystallin. Developmental analysis reveals a progressive, ventral to dorsal maturation of telencephalic meninges. Our studies present an unprecedented view of meningeal fibroblasts, providing a molecular profile of embryonic meningeal fibroblasts by layer that yield insights into mechanisms of meninges development and function.
2020-07-06 | GSE150219 | GEO
Project description:The meninges are important for brain development and pathology. Using single-cell RNA-sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared to their adult counterparts. We also identified novel meningeal microglia-like populations that appear to participate in white matter development. Early after hypoxic-ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell-resolution view of the importance of meningeal leukocytes at different stages of development in health and disease. DOI:10.1101/gad.348190.120
2021-07-23 | GSE173769 | GEO
Project description:Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders and can modulate neurodevelopment and behavior. While this has sparked great interest in the meninges, 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 sequencing, we assessed the differential long-term outcomes between young and aged mice following a TBI. In our scRNA-seq studies, we found that mild head trauma leads to an activation of type I interferon (IFN) signature genes in meningeal macrophages as well as the mobilization of multiple distinct sub-populations of meningeal macrophages expressing hallmarks of either classically activated or wound healing macrophages. We also revealed that dural fibroblasts in the meningeal compartment are highly responsive to TBI, and pathway analysis identified differential expression of genes linked to various neurodegenerative diseases. For reasons that remain poorly understood, the elderly are especially vulnerable to head trauma, where even mild injuries can lead to rapid 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 from mice that had received a mild TBI or Sham treatment 1.5 months prior. Notably, we found that aging alone induced massive 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 massive upregulation of immune-related genes and markedly reduced expression of genes involved in extracellular matrix remodeling and maintenance of cellular junctions. Overall, these findings illustrate the dynamic and complex transcriptional response of the meninges to mild head trauma. Moreover, we also reveal how aging modulates the meningeal response to TBI.
2022-12-22 | GSE206940 | GEO
Project description:Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders and can modulate neurodevelopment and behavior. While this has sparked great interest in the meninges, 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 sequencing, we assessed the differential long-term outcomes between young and aged mice following a TBI. In our scRNA-seq studies, we found that mild head trauma leads to an activation of type I interferon (IFN) signature genes in meningeal macrophages as well as the mobilization of multiple distinct sub-populations of meningeal macrophages expressing hallmarks of either classically activated or wound healing macrophages. We also revealed that dural fibroblasts in the meningeal compartment are highly responsive to TBI, and pathway analysis identified differential expression of genes linked to various neurodegenerative diseases. For reasons that remain poorly understood, the elderly are especially vulnerable to head trauma, where even mild injuries can lead to rapid 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 from mice that had received a mild TBI or Sham treatment 1.5 months prior. Notably, we found that aging alone induced massive 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 massive upregulation of immune-related genes and markedly reduced expression of genes involved in extracellular matrix remodeling and maintenance of cellular junctions. Overall, these findings illustrate the dynamic and complex transcriptional response of the meninges to mild head trauma. Moreover, we also reveal how aging modulates the meningeal response to TBI.
2022-12-22 | GSE206932 | GEO
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217312 | GEO
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217276 | GEO
Project description:Ectopic lymphoid tissue containing B cells forms in the meninges at late stages of human multiple sclerosis (MS) and when neuroinflammation is induced by interleukin (IL)-17 producing T helper (Th17) cells in rodents. B cell differentiation and the subsequent release of class-switched immunoglobulins have been speculated to occur in the meninges, but the exact cellular composition and underlying mechanisms of meningeal-dominated inflammation remain unknown. Here, we performed in depth characterization of meningeal vs. parenchymal Th17-induced rodent neuroinflammation. The most pronounced cellular and transcriptional differences between these compartments was the localization of B cells exhibiting a follicular phenotype exclusively to the meninges. Correspondingly, meningeal but not parenchymal Th17 cells, acquired a B cell-supporting phenotype and resided in close contact with B cells. This preferential B cell tropism for the meninges and the formation of meningeal ectopic lymphoid tissue was partially dependent on the expression of the transcription factor Bcl6 in Th17 cells, that is required in other T cell lineages to induce isotype class-switching in B cells. A function of Bcl6 in Th17 cells was only detected in vivo and was reflected by the induction of B cell-supporting cytokines, the appearance of follicular B cells in the meninges, and of immunoglobulin class-switching in the CSF. We, thus, identify the induction of a B cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a novel mechanism controlling compartment-specificity in neuroinflammation.
2021-07-30 | GSE178085 | GEO