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| Open AccessBacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models
The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD). Here, the authors show that Bacteroides fragilis contributes to AD pathogenesis in mouse models by suppressing immune-mediated microglial clearance of amyloid beta.
- Caroline Wasén
- , Leah C. Beauchamp
- & Howard L. Weiner
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Article
| Open AccessCXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis
Here, the authors demonstrate that CXCL5 expression is increased in ankle joints of gouty arthritis model mice. CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and joint inflammation.
- Chengyu Yin
- , Boyu Liu
- & Boyi Liu
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Article
| Open AccessSKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
Secretory autophagy (SA) plays a crucial role in neuroinflammation-driven neurodegeneration, through SKA2 and FKBP5. SKA2 regulation of SA can inhibit IL-1β release. Its dysfunction leads to neurodegeneration, and is linked to Alzheimer’s disease.
- Jakob Hartmann
- , Thomas Bajaj
- & Nils C. Gassen
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Article
| Open AccessAgeing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination
Factors limiting CNS remyelination with age are poorly understood. Here the authors show that aged Treg lose capacity to support CNS remyelination in mice, which can be restored in a young environment.
- Alerie Guzman de la Fuente
- , Marie Dittmer
- & Denise C. Fitzgerald
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Article
| Open AccessProfiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
- Aletta M. R. van den Bosch
- , Marlijn van der Poel
- & Jörg Hamann
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Article
| Open AccessRegulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue
Regulatory T cell (Treg) maintenance and function require IL-2, yet this cytokine is only present in low levels in vivo. In this study, the authors demonstrate that that Treg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.
- Hunter A. Martinez
- , Ievgen Koliesnik
- & Hedwich F. Kuipers
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Article
| Open AccessNon-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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Article
| Open AccessLarval microbiota primes the Drosophila adult gustatory response
How the larval environment influences the sensory characteristics of the future adult is largely unknown. Here, using Drosophila as a model, the authors show that the presence of certain bacterial species during the larval stage modify the gustatory capacities of the future adult flies.
- Martina Montanari
- , Gérard Manière
- & Julien Royet
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Article
| Open AccessAmyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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Article
| Open AccessBystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity
Many viral infections are linked to the development of neurological disorders. Here, Balint et al use a mouse model of Zika virus infection to show that it is immune cells (NKG2D+CD8+ T cells) that cause infection-associated paralysis, rather than the virus itself.
- Elizabeth Balint
- , Emily Feng
- & Ali A. Ashkar
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Article
| Open AccessINPP5D regulates inflammasome activation in human microglia
INPP5D/SHIP1 is a microglial-expressed gene that has been associated with Alzheimer’s disease through genetic studies. This study reveals that reduction in INPP5D activity induces activation of the NLRP3-inflammasome in human microglia.
- Vicky Chou
- , Richard V. Pearse II
- & Tracy L. Young-Pearse
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Article
| Open AccessAssociations of myeloid cells with cellular and humoral responses following vaccinations in patients with neuroimmunological diseases
Patients with autoimmune diseases require immunosuppressive treatments that affect their responses to infection and vaccination. Here, using mass cytometry, the authors to identify a role for myeloid cells in cellular and humoral responses following vaccination against SARS-CoV-2 in patients with neuroimmunological diseases.
- Meng Wang
- , Adeline Dehlinger
- & Chotima Böttcher
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Article
| Open AccessBrain-to-gut trafficking of alpha-synuclein by CD11c+ cells in a mouse model of Parkinson’s disease
Despite being implicated in several neurological diseases, the gut-brain axis remains poorly understood. Here the authors describe a mechanism of communication between the brain and the gut in a Parkinson’s disease mouse model mediated by CD11c+ macrophages.
- Rhonda L. McFleder
- , Anastasiia Makhotkina
- & Chi Wang Ip
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Article
| Open AccessMicroglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects
Demyelination is often suggested to cause axonal degeneration. Here, the authors study mice carrying distinct PLP defects and reveal how persistent ensheathment with perturbed myelin poses a risk for CD8 + T cell-driven axon loss and behavioral decline.
- Janos Groh
- , Tassnim Abdelwahab
- & Rudolf Martini
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Article
| Open AccessPolarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release
Microglia drastically change their morphology when reacting to pathological stimuli. Here, the authors study the molecular responses to stimulation and unravel cytoskeleton remodeling pathways that induce morphological and functional changes.
- Max Adrian
- , Martin Weber
- & Casper C. Hoogenraad
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessVE-cadherin in arachnoid and pia mater cells serves as a suitable landmark for in vivo imaging of CNS immune surveillance and inflammation
How the leptomeninges establish CNS compartments with different accessibility to immune cells and immune mediators remains unknown. Here, the authors show junctional localization of VE-cadherin in arachnoid and pia mater cells, which allows to visualize potential barrier properties of the leptomeninges in vivo.
- Josephine A. Mapunda
- , Javier Pareja
- & Britta Engelhardt
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Article
| Open AccessPD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation
Co-inhibitory signaling controls immune mechanisms in health and disease. The authors here show that in autoimmune neuroinflammation, astrocytic PD-L1 mitigates autoimmune neuroinflammation through interaction with PD1 expressing microglia.
- Mathias Linnerbauer
- , Tobias Beyer
- & Veit Rothhammer
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Article
| Open AccessTranslocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
TSPO PET imaging is widely used to quantify microglial activation. Here, the authors show that TSPO expression increases in activated rodent but not human microglia, implying that in humans TSPO informs on microglial density rather than activation status.
- Erik Nutma
- , Nurun Fancy
- & David R. Owen
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Article
| Open AccessMicroglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis
Microglial activation is critical for coordinating the immune response during neuroinflammation. Here, the authors demonstrate that the CD83 molecule intrinsically modulates microglial activity and restrains inflammatory processes in experimental autoimmune encephalomyelitis.
- Pia Sinner
- , Katrin Peckert-Maier
- & Andreas B. Wild
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Article
| Open AccessVγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males
Traumatic brain injury is not only a neurological but also an immunological condition in which multiple innate and adaptive immune cell types play roles. Here authors show in a mouse model that the Vγ4 subtype of the unconventional gamma-delta T cells promote neuroinflammation, while the Vγ1 subtype ameliorates immunopathology.
- Hadi Abou-El-Hassan
- , Rafael M. Rezende
- & Howard L. Weiner
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Article
| Open AccessWhole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Rosacea is a common, multi-factorial chronic inflammatory skin disorder. Here authors provide evidence of genetic predisposition by whole genome sequencing and whole exome sequencing of samples from familial cases, and by recapitulating a recurrent mutation in the LRRC4 gene in a mouse model, they find that neuron-derived vasoactive intestinal peptide is an important pathogenic factor for neurogenic inflammation in rosacea.’
- Zhili Deng
- , Mengting Chen
- & Ji Li
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Article
| Open AccessT cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS
Cryptococcus-associated immune reconstitution inflammatory syndrome is a condition found in immunocompromised patients on antiretroviral therapy and characterized by numerous symptoms, including pulmonary distress. Here, Kawano et al use a mouse model to characterize the processes underlying this pulmonary dysfunction.
- Tasuku Kawano
- , Jinyan Zhou
- & Makoto Inoue
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Article
| Open AccessBorder-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
Neuroinflammatory mechanisms are implicated in Parkinson disease. Here we identify border-associated macrophages (BAMs), as essential for the α-synuclein-mediated neuroinflammatory response via class II antigen presentation, and T cell infiltration.
- A. M. Schonhoff
- , D. A. Figge
- & A. S. Harms
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Article
| Open AccessGalectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease
In inflammatory arthritis, pain neurons communicate with spinal cord microglia to establish nociception. Here, the authors show that this communication is mediated by pain neurons releasing galectin-3, which activates microglia through TLR4. In a mouse model of Alzheimer’s disease, pain is attenuated because microglia lack expression of TLR4.
- George Sideris-Lampretsas
- , Silvia Oggero
- & Marzia Malcangio
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Article
| Open AccessVagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice
Coagulation factor VIII deficiency in hemophilia A disrupts clotting and prolongs bleeding. Here, the authors show that vagus nerve stimulation bypasses this defect and improves hemostasis in hemophilia A mice through a mechanism requiring acetylcholine-secreting ChAT+ T lymphocytes in spleen and α7nAChR on circulating platelets.
- Carlos E. Bravo-Iñiguez
- , Jason R. Fritz
- & Jared M. Huston
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Article
| Open AccessAntigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown
Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system are early hallmarks of multiple sclerosis. Here, the authors demonstrate that brain endothelial cells cross-present antigen to CD8+ T cells, thereby preventing their migration and initiating BBB breakdown.
- Sidar Aydin
- , Javier Pareja
- & Britta Engelhardt
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Article
| Open AccessNatural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine
The meningeal compartment communicates with the brain to modulate homeostatic functions. Here, the authors demonstrate that natural killer (NK) cells and innate lymphoid cells (ILC) 1 shape synaptic neuronal transmission and affect mouse behavior.
- Stefano Garofalo
- , Germana Cocozza
- & Cristina Limatola
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Article
| Open AccessNeonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment
Early life inflammation has been linked to neurodevelopmental outcomes. Here the authors show that in mice, neonatal immune challenge results in CD3 + T cell infiltration to brain parenchyma, and microglial activation, to a greater extent in males than females.
- Marius Schwabenland
- , Omar Mossad
- & Thomas Blank
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Perspective
| Open AccessAn aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
| Open AccessN-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model
Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.
- Stefano Suzzi
- , Tommaso Croese
- & Michal Schwartz
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Article
| Open AccessT cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles
Glioblastoma is a highly aggressive, and also the most common, brain tumour type in adults. Here, the authors generate a nanoparticle encapsulating the TLR7/8 agonist, R848, which induces tumour regression in mice by reprogramming myeloid cells independently of T and NK cells.
- Verena Turco
- , Kira Pfleiderer
- & Michael Platten
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Article
| Open AccessDeciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain
Perivascular macrophages (pvMs) are important for brain drainage and immune regulation. Here the authors analyse various reporter mouse strains for finer mapping of pvM subsets and lineage differentiation, and propose CX3CR1negative and CD45low as additional markers of intermediate pvMs for studying this heterogenous population.
- C. Siret
- , M. van Lessen
- & S. A. van de Pavert
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Article
| Open AccessDifferential compartmentalization of myeloid cell phenotypes and responses towards the CNS in Alzheimer’s disease
Multiple state-of-the-art analyses of immune cells in 117 blood, 117 cerebrospinal fluid, 13 choroid plexus and 13 brain parenchyma samples reveal differential characteristics of immune cells in different body compartments and different diseases.
- Camila Fernández Zapata
- , Ginevra Giacomello
- & Chotima Böttcher
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Article
| Open AccessT cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression
Amyotrophic lateral sclerosis (ALS) is a primary neurodegenerative disease, which is characterized by increased immune cell infiltration of the central nervous system. Here authors show that the phenotypic profile of T cells in the blood and cerebrospinal fluid of newly diagnosed ALS patients can predict disease progression, thus providing evidence that T cells contribute to disease pathology.
- Solmaz Yazdani
- , Christina Seitz
- & Fang Fang
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Article
| Open AccessCerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia.
- Jessica Gracias
- , Funda Orhan
- & Carl M. Sellgren
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Article
| Open AccessNeuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma
Responses to immune checkpoint blockade (ICB) in patients with glioblastoma are limited. Here the authors show that Calmodulin-Dependent Kinase Kinase 2 (CaMKK2) is expressed in tumor associated macrophages and neurons and is associated with resistance to ICB in preclinical models of glioblastoma.
- William H. Tomaszewski
- , Jessica Waibl-Polania
- & John H. Sampson
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Article
| Open AccessGenetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells
The role of the immune system in the pathogenesis of psychiatric disorders is unclear. Here, the authors show that genetic risk variants for multiple psychiatric disorders are enriched in regions of the genome active in the brain and in lymphoid cells, especially stimulated T cells, but not in myeloid cells.
- Mary-Ellen Lynall
- , Blagoje Soskic
- & Ed Bullmore
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Article
| Open AccessThe alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury
The neuroimmune interactions driving secondary degeneration in the injured spinal cord remain elusive. Here, the authors reveal that damaged microglia release IL-1α, resulting in neutrophil infiltration and the loss of mature oligodendrocytes through astrocytic and endothelial IL-1R1 in mice.
- Floriane Bretheau
- , Adrian Castellanos-Molina
- & Steve Lacroix
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Article
| Open AccessSingle cell and spatial transcriptomic analyses reveal microglia-plasma cell crosstalk in the brain during Trypanosoma brucei infection
Detailed insight into how the brain responds to Trypanosoma brucei infection is lacking. Here, single cell and spatial transcriptomics are integrated to characterise this response, identifying a unique crosstalk between microglia and plasma cells.
- Juan F. Quintana
- , Praveena Chandrasegaran
- & Annette MacLeod
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Article
| Open AccessRejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance
The authors discovered that proinflammatory senescent myeloid cells may recruit peripheral immune cells in the aged mouse brain. Their findings implicate senescent cell clearance as a strategy to counter aged brain inflammation and cognitive decline.
- Xu Zhang
- , Vesselina M. Pearsall
- & Marissa J. Schafer
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Article
| Open AccessChimeric GPCRs mimic distinct signaling pathways and modulate microglia responses
Understanding the function of GPCRs requires stimulation with their specific ligands. Here, the authors design chemogenetic G-protein coupled receptors that allows for the study of receptors without knowing the immediate ligand, and demonstrate its use for the β2-adrenergic receptor in microglia.
- Rouven Schulz
- , Medina Korkut-Demirbaş
- & Sandra Siegert
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Article
| Open AccessPregnancy-induced maternal microchimerism shapes neurodevelopment and behavior in mice
During pregnancy, maternal cells are transferred to the fetus, where they can reach the developing brain. In this study, the authors demonstrate that these maternal cells play an important role in neurodevelopment.
- Steven Schepanski
- , Mattia Chini
- & Petra C. Arck
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Article
| Open AccessMyasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma
Myasthenia Gravis and thymoma are frequently associated with patients suffering from both diseases. Here the authors perform single cell sequencing of thymoma and find that there are autoimmune antigens such as neuromuscular proteins expressed aberrantly in neuromuscular mTECs in patients with both diseases.
- Yoshiaki Yasumizu
- , Naganari Ohkura
- & Hideki Mochizuki
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Article
| Open AccessMicroglia coordinate cellular interactions during spinal cord repair in mice
Here the authors show, using microglia-specific depletion techniques and single cell transcriptomics, that optimal repair after murine spinal cord injury (SCI) requires microglia.
- Faith H. Brennan
- , Yang Li
- & Phillip G. Popovich
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Article
| Open AccessChondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury
Inflammation resolution failure is a pathological hallmark of spinal cord injury. Here, the authors show in rodents that chondroitin sulfate proteoglycans contribute to failed resolution by preventing immune cells at the injury core from converting to a pro-resolution phenotype, and this is mediated by TLR4.
- Isaac Francos-Quijorna
- , Marina Sánchez-Petidier
- & Elizabeth J. Bradbury
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Article
| Open AccessVersican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination
Ghorbani and colleagues describe versican-V1 as an inhibitor of remyelination using transgenic mice that illuminate new GFP + oligodendrocytes. Mechanisms of versican-V1 include the direct inhibition of oligodendrocytes, and elevating Th17 cells.
- Samira Ghorbani
- , Emily Jelinek
- & V. Wee Yong
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Article
| Open AccessTH17 cells promote CNS inflammation by sensing danger signals via Mincle
Mincle is a pattern recognition receptor that senses danger signals in innate immune cells. Here authors show in an experimental autoimmune encephalomyelitis mouse model that tissue damage triggers Mincle signaling on inflammatory helper T cells, leading to inflammasome-mediated IL-1β production and reinforced inflammation.
- Quanri Zhang
- , Weiwei Liu
- & Xiaoxia Li
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Article
| Open AccessPresenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα
Hyperimmunity is associated with Alzheimer disease. Here the authors show that the Presenilin 2 N141I mutation causes overproduction of clock-controlled cytokines and memory deficits through suppression of REV-ERBα gene by hypermethylation.
- Hyeri Nam
- , Younghwan Lee
- & Seong-Woon Yu