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Infection drives long-term meningeal engraftment by inflammatory monocytes that impair central nervous system immunity [II]

ABSTRACT: Tissue-resident macrophages have an embryonic origin, but are replenished under steady state conditions in some tissues by blood monocytes that can adopt genotypic and phenotypic features of the residents. However, little is known about the residency and functional properties of infiltrating macrophages after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of specialized macrophages that act as resident immune sentinels. Here we show that following lymphocytic choriomeningitis virus infection resident meningeal macrophages become activated by innate inflammatory cytokines, acquire viral antigen, and interact directly with infiltrating cytotoxic T lymphocytes (CTL), which leads to their depletion. Concurrently, the meninges are heavily infiltrated by peripherally-derived inflammatory monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. This engraftment leads to phenotypic and functional changes in the pool of resident meningeal macrophages that depends in part on IFNγ signaling. These changes include loss of bacterial and immunoregulatory sensors that impede subsequent CNS immune reactions. Collectively, these data indicate that peripheral monocytes can engraft the meninges after an inflammatory challenge, imprinting the compartment with long-term defects in immune function.

ORGANISM(S): Mus musculus

PROVIDER: GSE108647 | GEO | 2019/03/06

REPOSITORIES: GEO

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Infection drives long-term meningeal engraftment by inflammatory monocytes that impair central nervous system immunity [I]

Project description:Tissue-resident macrophages have an embryonic origin, but are replenished under steady state conditions in some tissues by blood monocytes that can adopt genotypic and phenotypic features of the residents. However, little is known about the residency and functional properties of infiltrating macrophages after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of specialized macrophages that act as resident immune sentinels. Here we show that following lymphocytic choriomeningitis virus infection resident meningeal macrophages become activated by innate inflammatory cytokines, acquire viral antigen, and interact directly with infiltrating cytotoxic T lymphocytes (CTL), which leads to their depletion. Concurrently, the meninges are heavily infiltrated by peripherally-derived inflammatory monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. This engraftment leads to phenotypic and functional changes in the pool of resident meningeal macrophages that depends in part on IFNγ signaling. These changes include loss of bacterial and immunoregulatory sensors that impede subsequent CNS immune reactions. Collectively, these data indicate that peripheral monocytes can engraft the meninges after an inflammatory challenge, imprinting the compartment with long-term defects in immune function.

2019-03-06 | GSE108467 | GEO

Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury

Project description:The meningeal space is occupied by a diverse repertoire of innate and adaptive immune cells. CNS injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation in CNS injury remains poorly understood. Here we describe group 2 innate lymphoid cells (ILC2s) as a novel cell type resident in the healthy meninges that is activated following CNS injury. ILC2s are present throughout the naïve mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile relative to lung ILC2s. After spinal cord injury, meningeal ILC2s are activated in an IL-33 dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild type lung-derived ILC2s into the meningeal space of IL-33R-/- animals improves recovery following spinal cord injury. These data characterize ILC2s as a novel meningeal cell type that responds to and functionally affects outcome after spinal cord injury, and could lead to new therapeutic insights for CNS injury or other neuroinflammatory conditions.

2016-12-13 | GSE90908 | GEO

Bacteria hijack a neuro-immune axis in meninges to facilitate brain invasion

Project description:The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.

2022-12-23 | GSE221681 | GEO

Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders [scBCR-seq]

Project description:The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single cell analyses, confocal 35 imaging, bone marrow chimeras and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvaria- meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that 40 populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells which may help maintain immune privilege within the CNS.

2021-06-01 | GSE174835 | GEO

Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders [scRNA-seq]

2021-06-01 | GSE174834 | GEO

A single-cell atlas reveals heterogeneity of meningeal immunity in a mouse model of Methyl CpG binding protein 2 deficiency

Project description:Methyl CpG binding protein 2 (MeCP2) is a DNA methylation reader protein, and mutations in MeCP2 are the major cause of Rett syndrome (RTT). Increasing evidence has shown that dysregulated immunity and chronic subclinical inflammation are linked to MeCP2 deficiency and contribute to RTT development and deterioration. The meninges surrounding the central nervous system (CNS) contain a wide repertoire of immune cells that participate in immune surveillance of the CNS and influence brain functions. However, the characterization and role of meningeal immunity in CNSs with MeCP2 deficiency remain poorly understood. We applied a single-cell sequence to profile Mecp2 deficient meningeal immune cells from the dura mater, which has been reported to have the most numerous meningeal immune cells in homeostasis. The data showed that the meninges of Mecp2-null mice contained the same diverse immune cell populations as control mice and showed an up-regulation of immune-related processes. B cell populations were great larger in Mecp2-null mice than in control mice, and the expression of genes coding for immune globulins was remarkably higher. For T cells, Mecp2 deficient meninges were more enriched in cytotoxic CD8+ T cells than in the control. With increased interferon-γ transcription in T and natural killer cells, meningeal macrophages showed less suppression and were more active in Mecp2 deficiency mice. Our study provides novel insights into meningeal immunity, which is a less studied aspect of neuroimmune interactions in Mecp2 mutated diseases and offers an essential resource for comparative analyses and data exploration for a better understanding of the functional role of meningeal immunity in RTT.

2022-12-29 | GSE221361 | GEO

Single cell transcriptomic analyses of the developing meninges reveal meningeal fibroblast diversity and function

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

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature [2D2 T cells]

Project description:Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

2018-09-18 | GSE99764 | GEO

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature

2018-09-18 | GSE99743 | GEO

Myelin-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner

Project description:B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG]mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+T helper 17 (Th17) cells in theCNS. Unusually, production of the Th17 maintenance factor IL-23 is observed from IgH[MOG]CNS-infiltrating and meningeal B cells, andin vivoblockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5-T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges inan IL-23 dependent manner.

2024-05-14 | GSE267422 | GEO

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