Symposium
Neuroinflammation and the Blood Brain Interface: New findings in brain pathology
シンポジウム
Neuroinflammation and the Blood Brain Interface: New findings in brain pathology |
|---|
| 7月27日（土）14:25～14:55 第2会場（朱鷺メッセ 2F メインホールA）
3S02a-1
Regulating Neurological Disorders via the Meningeal Lymphatic System
Antoine Louveau（Louveau Antoine）1，Jonathan Kipnis（Kipnis Jonathan）2
1Lerner Research Institute Cleveland Clinic
2University of Virginia
The central nervous system (CNS) is considered an immune privilege organ, primarily due to its lack of lymphatic system. Contrary to the CNS, its surrounding i.e. the meninges have recently been shown to harbor a conventional and functional lymphatic system capable of draining fluid (CSF). Multiple questions remains to better understand the function of the meningeal lymphatic vasculature and its potential role in regulating normal brain function and neurological disorders.
We found that the meningeal lymphatic is a major route for drainage of CSF macromolecules and meningeal immune cells into the cervical lymph nodes and that their ablation results in the accumulation of circulating immune cells in the meninges, the abrogation of parenchymal CSF circulation and results in mild cognitive impairment. Moreover, we discovered that meningeal lymphatic function is affected during aging and that restoration of meningeal lymphatic function using growth factor is sufficient to restore CSF flux into the brain and restore age-associated cognitive decline. In models of neurodegeneration (Alzheimer's disease), we discovered that meningeal lymphatic malfunction is worsening disease pathology while diminishing disease pathology in models of brain autoimmunity (Experimental Autoimmune Encephalomyelitis). Overall these data are demonstrating a central and major role for the meningeal lymphatic system in regulating physiological and pathological CNS and might represent a promising therapeutical target to treat neurological disorders. | | 7月27日（土）14:55～15:25 第2会場（朱鷺メッセ 2F メインホールA）
3S02a-2
The Neuroimmune Axes of the Blood-brain Interface
William Allen Banks（Banks William Allen）
Veterans Affairs and U of Washington - Seattle
The vascular blood-brain barrier (BBB) is a modified capillary bed that prevents the unregulated exchange of substances between the blood and the interstitial fluid of the brain. As such, it establishes the brain as an immune-privileged area. Additionally, the BBB regulates several types of neuroimmune interactions between the brain and blood and so acts more as a blood-brain interface (BBI) than exclusively as a barrier (Pharm Rev 70:278-314, '18). The five major known categories of neuroimmune BBI interactions are: 1) neuroimmune regulation of vascular BBB integrity; 2) immune modulation of BBI properties; 3) transport of neuroimmune substances across the BBB; 4) immune cell trafficking across the vascular BBB and choroid plexus; 5) neuroimmune secretions by the barrier cells that comprise the BBB's. These neuroimmune axes integrate communications between barrier cells, among other cells of the neuroimmune axis, and with circulating immune and peripheral cells via the blood stream. The neuroimmune axes are important in disease states as well as normal physiological functions and offer strategies for the development of CNS therapeutics. As examples: i) disruption of the BBB from several causes is mediated by neuroimmune substances, including cytokines, nitric oxide, and prostaglandins; ii) inflammatory events stimulate cytokine secretion by barrier cells that act in autocrine or paracrine fashion to enhance the transfer of HIV-1 across the BBB; iii) modulation of the efflux transporters low-density lipoprotein receptor-related protein and P-glycoprotein by neuroinflammatory events increases retention of amyloid beta protein, thus contributing to an Alzheimer's phenotype; iv) transport of cytokines from blood-to-brain can enhance disease processes as illustrated by the role of tumor necrosis factor-alpha for both Parkinson's disease and chemobrain or can be important in therapy as illustrated by transport of interleukin-1 in the treatment of febrile infection-related epilepsy syndrome (FIRES), an intractable seizure syndrome that occurs in children. These five known neuroimmune axes act singly and together, connecting the central nervous and immune systems in communication that is regulated by the BBI. | | 7月27日（土）15:25～15:55 第2会場（朱鷺メッセ 2F メインホールA）
3S02a-3
Meningeal and capillary mediation of brain inflammation
Mike Dragunow（Dragunow Mike）
University of Auckland
Brain inflammation is a complex process that involves multiple cell types that impacts the initiation and progression of many chronic brain disorders as well as injuries, epilepsies and stroke. Most studies have focused on the role of microglia and astrocytes in brain inflammation. We and others have shown that cells making up brain capillaries (pericytes and endothelial cells) as well as the meninges and choroid plexus are also critical for brain inflammation and these tissues may provide the initial links and conduits between systemic inflammation and brain inflammation.
Because the use of animal models has so far failed to predict drug efficacy for disease-modification in patients suffering from brain disorders we have established a human brain cell culture facility to grow, study and test human brain cells for neuropharmacology research and CNS drug development (see https://www.fmhs.auckland.ac.nz/en/faculty/cbr/our-centre/the-hugh-green-biobank.html). We have also set up a CNS drug discovery and validation platform using human brain tissue microarray, automated microscopy and automated high content screening (www.neurovalida.com)
Using these platforms we have developed in vitro models of inflammation by exposing patient-derived dissociated cultures of adult human brain pericytes and endothelial cells, as well as explant cultures of human meninges and choroid plexus to inflammatory mediators such as interleukin 1β and interferonγ, and to lipopolysaccharide. Using RNAseq and secretome methods we have identified a number of transcription factors, chemokines and many other signaling molecules produced & secreted by human pericytes, endothelia, meninges and choroid plexus. By screening an FDA-approved library of 1280 compounds we have also identified a class of compounds that strongly inhibit inflammation generated in these human brain cells and tissues.
This combined work will be described and the implications for treating human brain disorders discussed. | | 7月27日（土）15:55～16:20 第2会場（朱鷺メッセ 2F メインホールA）
3S02a-4
Histological architecture underlying brain-immune cell-cell interactions
Atsuyoshi Shimada（Shimada Atsuyoshi）
Kyorin University Faculty of Health Sciences
The central nervous system is interactive with the peripheral immune system. Our studies using adult bone marrow chimeric mice determined the site of cell-cell interactions between brain and immune cells under non-inflammatory conditions: choroid plexus (CP), leptomeninges, perivascular space and circumventricular organs (CVOs). In addition, bone marrow-derived cells appear in specific discrete brain parenchymal regions and exhibit multiple ramified processes with myeloid lineage differentiation. Most of these regions are adjacent to the attachments of CP in which the brain parenchyma is extremely thin and consists of astrocytic elongated processes situated in the narrow channel between the ependyma and pia. These processes express CX3CL1, a possible chemoattractant for myeloid lineage cells. Therefore, the CP and the attachments as well as the leptomeninges, perivascular space and CVOs provide the brain-immune interface in adult mice. In systemic inflammation such as lipopolysaccharide (LPS)-induced endotoxemia, the signaling using IL-1β derived from CP macrophages and IL-1 receptors on CP stromal cells is the immediate reaction. The reaction triggers cytokine-mediated cell-cell interactions between CP stromal and epithelial cells. Then, cells of the brain-immune interface respond to endotoxemia by producing cytokines including CCL2, CXCL1, CXCL2, etc. earlier than parenchymal cells. In the parenchyma, astrocytes play a key role in responding to the signals by using endfeet located in close apposition to the interface cells. Thereafter, stimulated astrocytes produce other cytokines, resulting in changes in the brain microenvironment in adult mice. Our ongoing studies using mice at postnatal day 1 (P1) suggest that LPS-induced endotoxemia induces macrophages in the CP stroma and cephalic mesenchyme but not parenchymal microglia to produce IL-1β. Since the developmental stage of the brain in P1 mice corresponds to that in human fetus around 22 weeks of gestational age, cephalic mesenchymal macrophages that have responded to systemic inflammation may migrate into the brain parenchyma to give rise to microglia. If such microglia retain the proinflammatory signature during the migration, it may explain why inflammatory responses persist in premature brain, resulting in adverse neurological outcome. I discuss the importance of histological architecture to understand the brain-immune cell-cell interactions in inflammatory conditions. | |
|
|
