Meningeal lymphatics, immunity and neuroinflammation

Frederick, Natalie M.; Louveau, Antoine

doi:10.1016/j.conb.2019.11.010

Cited by 23 publications

(26 citation statements)

References 37 publications

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“…In contrast, the meninges surrounding the brain consist of numerous immune cells even under homeostatic conditions, including T lymphocytes, macrophages, monocytes, DCs, and neutrophils. 30,31 When an ischemic injury occurs, the necrotic cells release damage-associated molecular patterns (DAMPs) such as HMGB1 to the extracellular environment and activate microglial cells. 15,32 Subsequently, the activated microglia in middle cerebral artery occlusion (MCAO) mice secrete substantial proinflammatory mediators such as TNF-α, IL-1β, reactive oxygen species, and inducible NOS to amplify neuroinflammation.…”

Section: Ischemic Strokementioning

confidence: 99%

“…With the protection of the BBB, the brain is described as an “immune‐privileged organ” due to the absence of immune cells, except for microglia under physiologic conditions. In contrast, the meninges surrounding the brain consist of numerous immune cells even under homeostatic conditions, including T lymphocytes, macrophages, monocytes, DCs, and neutrophils 30,31 . When an ischemic injury occurs, the necrotic cells release damage‐associated molecular patterns (DAMPs) such as HMGB1 to the extracellular environment and activate microglial cells 15,32 .…”

Section: Ischemic Strokementioning

confidence: 99%

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The lymphatic drainage system of the CNS plays a role in lymphatic drainage, immunity, and neuroinflammation in stroke

Chen

Wang

et al. 2021

Journal of Leukocyte Biology

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The lymphatic drainage system of the central nervous system (CNS) plays an important role in maintaining interstitial fluid balance and regulating immune responses and immune surveillance. The impaired lymphatic drainage system of the CNS might be involved in the onset and progression of various neurodegenerative diseases, neuroinflammation, and cerebrovascular diseases. A significant immune response and brain edema are observed after stroke, resulting from disrupted homeostasis in the brain.Thus, understanding the lymphatic drainage system of the CNS in stroke may lead to the development of new approaches for therapeutic interventions in the future. Here, we review recent evidence implicating the lymphatic drainage system of the CNS in stroke.

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Section: Ischemic Strokementioning

confidence: 99%

Section: Ischemic Strokementioning

confidence: 99%

The lymphatic drainage system of the CNS plays a role in lymphatic drainage, immunity, and neuroinflammation in stroke

Chen

Wang

et al. 2021

Journal of Leukocyte Biology

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“…The meninges are a delicate three-layer structure consisting of the dura, arachnoid and pia mater. In addition to grossly isolating the CNS from the periphery, the meninges are an immunologically active organ that play an important role in CNS immune surveillance by allowing peripheral immune cells to sample brain-derived antigens without directly accessing the parenchyma during homeostatic states (Engelhardt and Ransohoff, 2005;Siffrin et al, 2009;Mundt et al, 2019;Frederick and Louveau, 2020). Macrophages are thought to be the most abundant immune cell in murine meninges during steady-state, but populations of T-cells, B-cells, plasma cells (PCs), dendritic cells (DCs), monocytes, neutrophils, natural killer (NK) cells, and γδ T-cells have also been identified (Radjavi et al, 2014;Van Hove et al, 2019;Fitzpatrick et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The glymphatics system is a glial-dependent mechanism that relies on the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) to deliver substances across the brain parenchyma and clear CNS waste into systemic circulation (Louveau et al, 2017;Benveniste et al, 2019). CSF flows into the periarterial space from the subarachnoid space (SAS) where it diffuses into the parenchyma (Frederick and Louveau, 2020). This influx of CSF, drives the interstitial fluid (ISF) into the CSF within the perivenous space where it is cleared into the cervical lymph nodes (Alves de Lima et al, 2020;Frederick and Louveau, 2020;Papadopoulos et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…CSF flows into the periarterial space from the subarachnoid space (SAS) where it diffuses into the parenchyma (Frederick and Louveau, 2020). This influx of CSF, drives the interstitial fluid (ISF) into the CSF within the perivenous space where it is cleared into the cervical lymph nodes (Alves de Lima et al, 2020;Frederick and Louveau, 2020;Papadopoulos et al, 2020). (F) Meningeal Lymphatics.…”

Section: Introductionmentioning

confidence: 99%

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Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Mitchell

Shireman

Potchanant

et al. 2021

Front. Cell. Neurosci.

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According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.

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Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology

Agrawal

Baulch

Madan

et al. 2022

Cell. Mol. Life Sci.

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Alzheimer’s disease (AD) is associated with dysregulated immune and inflammatory responses. Emerging evidence indicates that peripheral immune activation is linked to neuroinflammation and AD pathogenesis. The present study focuses on determining the role of IL-21 in the pathogenesis of AD using human samples and the 5xFAD mice model. We find that the levels of IL-21 are increased in the periphery of both humans and mice in AD. In addition, the proportions of IL-21 target cells, Tfh and B plasma cells as well as activation of monocytes is increased in PBMCs from AD and mild cognitively impaired (MCI) subjects as compared to age-matched controls, indicating immune activation. In contrast, the percentage of B1 cells that control inflammation is decreased. These changes are due to IL-21 as the expression of IL-21 receptor (IL-21R) is higher on all these cells in AD. Furthermore, treatment with recombinant IL-21 in AD mice also leads to similar alterations in Tfh, B, B1, and macrophages. The effect of IL-21 is not confined to the periphery since increased expression of IL-21R is also observed in both humans and mice hippocampus derived from the AD brains. In addition, mice injected with IL-21 display increased deposition of amyloid beta (Aβ) plaques in the brain which is reduced following anti-IL-21R antibody that blocks the IL-21 signaling. Moreover, activation of microglia was enhanced in IL-21-injected mice. In keeping with enhanced microglial activation, we also observed increased production of pro-inflammatory cytokines, IL-18 and IL-6 in IL-21-injected mice. The microglial activation and cytokines were both inhibited following IL-21R blockage. Altogether, IL-21 escalates AD pathology by enhancing peripheral and brain immune and inflammatory responses leading to increased Aβ plaque deposition. Graphical abstract IL-21 impacts AD neuropathology by enhancing peripheral and neuronal immune activation, inflammation, and Aβ plaque deposition. Increased levels of IL-21 in the circulation of AD and MCI subjects enhances the proportions of Tfh and B plasma cells indicative of peripheral immune activation. On the other hand, the proportions of B1 cells that help reduce inflammation and clear Aβ are reduced. In addition to the periphery, IL-21 also acts on the brain via IL-21 receptor, IL-21R that displays increased expression in the hippocampi of AD and MCI subjects. IL-21 enhances the activation of microglia, induces the secretion of pro-inflammatory cytokines and deposition of Aβ plaques in the brain in AD.

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Meningeal lymphatics, immunity and neuroinflammation

Cited by 23 publications

References 37 publications

The lymphatic drainage system of the CNS plays a role in lymphatic drainage, immunity, and neuroinflammation in stroke

The lymphatic drainage system of the CNS plays a role in lymphatic drainage, immunity, and neuroinflammation in stroke

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology

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