Meningeal lymphoid structures are activated under acute and chronic spinal cord pathologies
Ontology highlight
ABSTRACT: Tertiary lymphoid structures (TLS) are organized aggregates of B and T cells formed ectopically during different life periods in response to inflammation, infection, or cancer. Here, we describe formation of structures reminiscence of TLS in the spinal cord meninges under several central nervous system (CNS) pathologies. Following acute spinal cord injury, B and T lymphocytes locally aggregate within the meninges to form TLS, which continue to accumulate during the late phase of repair, with a negative impact on subsequent pathological conditions, such as experimental autoimmune encephalomyelitis. Using a chronic model of spinal cord pathology, the mSOD1 mouse model of amyotrophic lateral sclerosis, we further showed by single cell RNA-sequencing that a meningeal lymphocyte niche forms, with a unique organization and activation state, including accumulation of pre-B cells in the spinal cord meninges. Such a response was not found in the CNS-draining cervical lymph nodes. The present findings suggest that a unique immune response develops in the meninges during various neurological pathologies in the CNS, a reflection of its immune privileged nature.
Project description:2nd generation sequencing was used to compare expression profiles of MBP-specific T cells retrieved from blood, CSF, spinal cord meninges and parenchyma. The overall expression profiles were found to be very similar.However, genes regulated during T cell activation were found to be upregulated in T cells from spinal cord meninges and parenchyma compared to blood and CSF. 2nd generation sequencing of MBP-specific T cells retrieved from blood and CNS compartments during experimental autoimmune encephalomyelitis
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.
Project description:We used single-cell RNA sequencing to profile immune cells in the injured spinal cord parenchyma and lymphatic endothelial cells in the spinal cord meninges from young and aged mice. This help us understand the heterogeneity of the immune response after injury and how it is altered in aging. Moreover, the data obtained from the spinal cord meninges provides novel molecular insights into how the meninges may contribute to the repair process.
Project description:We used single-cell RNA sequencing to profile immune cells in the injured spinal cord parenchyma and lymphatic endothelial cells in the spinal cord meninges from young and aged mice. This help us understand the heterogeneity of the immune response after injury and how it is altered in aging. Moreover, the data obtained from the spinal cord meninges provides novel molecular insights into how the meninges may contribute to the repair process.
Project description:We used single-cell RNA sequencing to profile immune cells in the injured spinal cord parenchyma and lymphatic endothelial cells in the spinal cord meninges from young and aged mice. This help us understand the heterogeneity of the immune response after injury and how it is altered in aging. Moreover, the data obtained from the spinal cord meninges provides novel molecular insights into how the meninges may contribute to the repair process.
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
Project description:2nd generation sequencing was used to compare expression profiles of MBP-specific T cells retrieved from blood, CSF, spinal cord meninges and parenchyma. The overall expression profiles were found to be very similar.However, genes regulated during T cell activation were found to be upregulated in T cells from spinal cord meninges and parenchyma compared to blood and CSF.
Project description:In homeostasis, because of the blood-brain barrier, immune cells rarely infiltrate the central nervous system (CNS). However, after spinal cord injury (SCI), many cells, including both myeloid and T cells, infiltrate the spinal cord. However, the role immune cells play in SCI remains controversial. We are curious whether after SCI there are self-peptides that are released and sensed by T cells that then modulate response to CNS injury.
Project description:Combining proteomics and systems biology analyses, we demonstrated that neonatal microglial cells derived from two different CNS locations (cortex and spinal cord) displayed different phenotypes upon different physiological or pathological conditions. These cells also exhibited great variability in terms of both cellular and small extracellular vesicles (sEVs) protein contents and levels. Bioinformatics data analysis showed that the cortical microglia had anti-inflammatory and neurogenesis/tumorigenesis properties, while the spinal cord microglia was rather involved in inflammatory response process. Of interest, while both sEVs microglia sources enhanced growth of DRGs axons, only the spinal cord-derived sEVs microglia under LPS stimulation significantly attenuated glioma proliferation. These results were confirmed through neurite outgrowth assays in DRGs cell line and glioma proliferation analysis in 3D spheroid cultures. Results from these in vitro assays indicated that the microglia localized at different CNS regions can ensure different biological functions. Together, these works indicate that neonatal microglia locations regulate their physiological and pathological functional fates, and could explain the high prevalence of brain vs. spinal cord glioma in adults.