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| Open AccessNon-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes
Studies in animal models have visualized drainage of interstitial or cerebrospinal fluid via lymphatic vessels, but there is limited data on in humans. Here, the authors non-invasively visualize lymphatic structures in the human brain, including evidence of lymphatic flow from cranial nerves to cervical lymph nodes, and differences by age and sex, without use of contrast agents.
- Mehmet Sait Albayram
- , Garrett Smith
- & Onder Albayram
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Article
| Open AccessDNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo
Using gene silencing to regulate lymphocyte function is a promising therapeutic approach for autommunity, inflammation and cancer. Here the authors use a heteroduplex oligonucleotide for improved potency, efficacy and longer retention times.
- Masaki Ohyagi
- , Tetsuya Nagata
- & Takanori Yokota
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| Open AccessTau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.
- Meihua Jin
- , Hiroki Shiwaku
- & Hitoshi Okazawa
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Article
| Open AccessInterferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy
Studies on interferon-driven brain pathology have so far been hampered by the lack of appropriate animal models. Here the authors characterize RNASET2-deficient mice and show that neuroinflammation and brain atrophy are IFNAR1-dependent.
- Matthias Kettwig
- , Katharina Ternka
- & Jutta Gärtner
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Article
| Open AccessOPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection
During herpesvirus infection, most individuals intrinsically suppress a primary infection and therewith preclude potential damage or neurodegeneration of the CNS. Here, Ames et al. show that Optineurin (OPTN), a conserved autophagy receptor, restricts HSV-1 spread, degrades viral VP16 through autophagy and is neuroprotective against HSV infection in vivo.
- Joshua Ames
- , Tejabhiram Yadavalli
- & Deepak Shukla
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| Open AccessSelective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models
- Debashis Dutta
- , Malabendu Jana
- & Kalipada Pahan
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Article
| Open AccessBeige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice
Visceral adiposity is a risk factor for cognitive decline, but subcutaneous adipose tissue (SAT) is not and may be protective. Here, the authors show that beige adipocytes are indispensable for the neuroprotective effects of SAT. Beige fat knockout mice were more susceptible to the neuroimmune and cognitive effects of obesity, and in normal mice, SAT transplants protected against chronic obesity via beige fat-dependent mechanisms.
- De-Huang Guo
- , Masaki Yamamoto
- & Alexis M. Stranahan
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Article
| Open AccessNociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection
Herpes simplex virus 1 (HSV-1) is a neurotropic virus that often cause pain via the induction of ulcer or blisters. Here the authors show, in mouse models of HSV-1 infection, that the pain-perceiving nociceptor Nav1.8+ neurons contribute to regulating both innate and adaptive immune responses against HSV-1, thereby offering a potential target for therapy.
- Jessica Filtjens
- , Anais Roger
- & Sophie Ugolini
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Article
| Open AccessTherapeutic B-cell depletion reverses progression of Alzheimer’s disease
Alzheimer’s disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.
- Ki Kim
- , Xin Wang
- & Arya Biragyn
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Article
| Open AccessActivation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice
GPR37 is expressed in macrophages, and has been implicated in resolution of inflammatory pain. Here the authors show that GPR37 can modulate sepsis in several animal models.
- Sangsu Bang
- , Christopher R. Donnelly
- & Ru-Rong Ji
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Article
| Open AccessIntegration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
This study integrates Alzheimer’s disease (AD) GWAS data with myeloid cell genomics, and reports that myeloid active enhancers are most burdened by AD risk alleles. The authors also nominate candidate causal regulatory elements, variants and genes that likely modulate the risk for AD.
- Gloriia Novikova
- , Manav Kapoor
- & Alison M. Goate
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Article
| Open AccessPersistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling
The transcriptional adaptation processes of harmful self-reactive CD8+ T cells in the central nervous system are not well understood. Here the authors use a system in which self-reactive and virally generated CD8+ T cells are directly compared in vivo and demonstrate that TOX expression contributes to maintenance of auto-reactive CD8+ T cells through alteration of chromatin accessibility.
- Nicolas Page
- , Sylvain Lemeille
- & Doron Merkler
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Article
| Open AccessA CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis
A better understanding of how multiple sclerosis (MS) can relapse and remit is needed for the identification of biomarkers and better therapeutics. Here the authors identify a CD8 + NK cell population in patients with relapsing remitting MS and validate its association with clinical outcome.
- Eoin F. McKinney
- , Iona Cuthbertson
- & Kenneth G. C. Smith
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| Open AccessCatalytically potent and selective clusterzymes for modulation of neuroinflammation through single-atom substitutions
Artificial enzymes with reprogrammed and augmented catalytic activity and substrate selectivity have emerged to tackle limitations of noble metals or transition metal oxides. Here, the authors report Au25 clusterzymes which are endowed with high catalytic activity and selectivity in a range of enzyme-mimicking reactions.
- Haile Liu
- , Yonghui Li
- & Xiao-Dong Zhang
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Article
| Open AccessEarly-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling
Early life trauma has been associated with multiple sclerosis, but the causal link is unclear. Here the authors show in mice that early life trauma can result in IFN-β-resistant EAE as a result of β-adrenergic desensitization in immune cells and that a β1 adrenergic receptor agonist can reverse this susceptibility.
- Yee Ming Khaw
- , Danish Majid
- & Makoto Inoue
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Article
| Open AccessSingle cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .
- Marta Olah
- , Vilas Menon
- & Philip L. De Jager
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Article
| Open AccessInterleukin-1 receptor-induced PGE2 production controls acetylcholine-mediated cardiac dysfunction and mortality during scorpion envenomation
Cardiac dysfunction is a major complication that precedes death after scorpion envenomation. Here, authors show that heart failure and mortality are caused by excessive acetylcholine release, which requires IL-1R-dependent PGE2 production. Dexamethasone treatment effectively inhibits cardiac dysfunction and mortality.
- Mouzarllem B. Reis
- , Fernanda L. Rodrigues
- & Lúcia H. Faccioli
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| Open AccessMeningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis
Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.
- Ashley C. Bolte
- , Arun B. Dutta
- & John R. Lukens
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| Open AccessCircadian control of brain glymphatic and lymphatic fluid flow
Glymphatic function is increased during the rest phase while more cerebrospinal fluid (CSF) drains directly to the lymphatic system during the active phase. The water channel aquaporin-4 supports these endogenous, circadian rhythms in CSF distribution.
- Lauren M. Hablitz
- , Virginia Plá
- & Maiken Nedergaard
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Article
| Open AccessBlood substitution therapy rescues the brain of mice from ischemic damage
Acute stroke causes complex, pathological, and systemic responses which remain challenging to treat. Here, the authors show that substituting the blood of stroke model mice with whole-blood from naive healthy donor mice reduces infarct volume and improves neurological deficits.
- Xuefang Ren
- , Heng Hu
- & James W. Simpkins
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Article
| Open AccessSpinal cord injury causes chronic bone marrow failure
Spinal cord injury (SCI) often leads to immune dysfunction, but mechanistic insights are still lacking. Here the authors show that SCI alters chemokine signaling and induces long, persisting defects in hematopoietic stem and progenitor cell migration, thereby entrapping them in the bone marrow and disrupting peripheral immune homeostasis.
- Randall S. Carpenter
- , Jessica M. Marbourg
- & Phillip G. Popovich
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Article
| Open AccessGasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection
Control over T. gondii infection in the brain involves microglial cells, but how these cells execute this control is not clear. Here the authors show that unlike IL-1β dominant macrophages, microglia are primed for gasdermin-D-dependent IL-1α production that is critical for protection against T. gondii infection.
- Samantha J. Batista
- , Katherine M. Still
- & Tajie H. Harris
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Article
| Open AccessThe TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Here, the authors show that microglia-specific deletion of TSPO and chemical inhibition of TSPO prevent neuroinflammation and vascular damage in a mouse model of AMD.
- Anne Wolf
- , Marc Herb
- & Thomas Langmann
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| Open AccessPeripheral nerve resident macrophages share tissue-specific programming and features of activated microglia
The characteristics of immune cells in the peripheral nervous system (PNS) are not fully understood. Here the authors examine the transcriptomic profile and ontogeny of macrophages from the PNS, show they are derived from both embryonic and hematopoietic precursors, and that they have some shared features with microglia.
- Peter L. Wang
- , Aldrin K. Y. Yim
- & Gwendalyn J. Randolph
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Article
| Open AccessPTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies
Neuroinflammation has been proposed to accompany the peripheral inflammation observed in PTSD. Here, authors find lower in vivo and postmortem levels of neuroimmune marker TSPO (translocator protein) in PTSD, in association with greater PTSD severity and higher plasma CRP.
- Shivani Bhatt
- , Ansel T. Hillmer
- & Kelly P. Cosgrove
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| Open AccessN-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease
Neuronal sphingosine kinase 1 (SphK1) acetylates COX2 which is needed for microglial phagocytosis activity, and release of pro-resolving mediators (SPMs) from neurons. Here the authors examine how SphK1-mediates COX2 acetylation, and how this leads to increased secretion of SPMs from neurons in the context of Alzheimer’s disease models.
- Ju Youn Lee
- , Seung Hoon Han
- & Jae-sung Bae
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Article
| Open AccessMALT-1 mediates IL-17 neural signaling to regulate C. elegans behavior, immunity and longevity
IL-17 is a pro-inflammatory molecule that can also regulate neural circuit function. Here the authors use C. elegans to show that the paracaspase MALT-1 lies downstream of IL-17 signaling and regulates many aspects of C. elegans biology, including escape behavior, associative learning, immunity and longevity.
- Sean M. Flynn
- , Changchun Chen
- & Mario de Bono
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Article
| Open AccessNatural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis
Neuroimmune interactions are important in amyotrophic lateral sclerosis (ALS). Here the authors characterize the role of NK cells in mouse models of ALS, and in patient tissue.
- Stefano Garofalo
- , Germana Cocozza
- & Cristina Limatola
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Article
| Open AccessP2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice
P2X7 receptors are purinergic receptors with pro-inflammatory functions. Here, the authors show that inhibition of leukocyte P2X7 receptors reduces dendritic spine pathology and social behavioral deficits in a mouse model of Rett syndrome.
- Juan Mauricio Garré
- , Hernandez Moura Silva
- & Guang Yang
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Article
| Open AccessLupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory
Systemic lupus erythematosus (SLE) is an autoimmune disorder which can have neurological manifestations, including autoantibody targeting of the NMDA receptor. In this study, the authors GluN2A subunit is a target of SLE autoantibodies, using sample derived from patient.
- Kelvin Chan
- , Jacquelyn Nestor
- & Lonnie P. Wollmuth
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Article
| Open AccessHeterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas
Modeling patient-individual resistance to immunotherapy is challenging. Here, the authors use a syngeneic experimental hypermutated orthotopic glioma model to define radiological and biological features that can predict or explain the mechanistic differences between responders and non-responders to immunotherapy.
- Katrin Aslan
- , Verena Turco
- & Michael Platten
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Article
| Open AccessMicroglial activation increases cocaine self-administration following adolescent nicotine exposure
Adolescents are particularly sensitive to nicotine. Here the authors show that in mice, microglial activation contributes to the enhanced sensitivity to cocaine caused by nicotine exposure in young mice.
- K. E. Linker
- , M. Gad
- & F. M. Leslie
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Article
| Open AccessDorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain
Interactions among spinal dorsal horn neurons and microglia contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. The authors show that depletion of macrophages in the dorsal root ganglia prevents and reverses ongoing nerve injury-induced hypersensitivity.
- Xiaobing Yu
- , Hongju Liu
- & Allan I. Basbaum
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Article
| Open AccessCD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome
Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.
- Catharina C. Gross
- , Céline Meyer
- & Roland Liblau
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| Open AccessIn vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
T cells from narcolepsy patients were recently reported to recognize hypocretin, a wakefulness-promoting neurohormone, suggesting autoimmune origin of the disease. Here the authors show that hypocretin-specific T cells expand both in healthy controls and in narcolepsy patients, and identify preliminary features that may distinguish them.
- Wei Jiang
- , James R. Birtley
- & Elizabeth D. Mellins
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Article
| Open AccessDietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology
Food intake shapes intestinal microbiome composition, which in turn shapes adaptive immune responses. Here the authors show that dietary tryptophan restriction (DTR) protects mice from subsequent autoimmune neuropathology challenge by altering intestinal microbiota, highlighting the potential of diet-regulated microbiota to prevent immune pathology.
- Jana K. Sonner
- , Melanie Keil
- & Michael Platten
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Article
| Open AccessBlunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease
Resolvins are endogenous lipids with pro-resolving activity. Here the authors find that rats overexpressing human α-synuclein show defects in dopamine signalling before dopamine cell loss, and that this is associated with low Resolvin D1 levels and neuroinflammation.
- Paraskevi Krashia
- , Alberto Cordella
- & Nicola Biagio Mercuri
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Article
| Open AccessOligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination
In multiple sclerosis (MS), antigen-presenting cells inducing cytotoxic T cell response against mature oligodendrocytes remain to be identified. Here the authors show that oligodendrocyte precursors cross-present antigen taken up from mature oligodendrocytes, and are targeted by cytotoxic T cells in cell culture and in an animal model of MS.
- Leslie Kirby
- , Jing Jin
- & Peter A. Calabresi
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Article
| Open AccessDeletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
The lineage-specific receptor CSF1R controls macrophage development and homeostasis. Here the authors show that deletion of a conserved Csf1r enhancer (FIRE) selectively depletes brain microglia and resident macrophages in the epidermis, kidney, heart and peritoneum of otherwise healthy mice.
- Rocío Rojo
- , Anna Raper
- & Clare Pridans
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Article
| Open AccessSoluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model
TREM2 is a genetic risk factor for Alzheimer’s disease, and soluble TREM2 (sTREM2) in the CSF correlates with AD progression. Here the authors study the role of sTREM2 in a mouse model of Alzheimer’s disease, and find it reduces amyloid accumulation and increases the numbers of plaque-associated microglia which correlates with improved behavioural function in the mice.
- Li Zhong
- , Ying Xu
- & Xiao-Fen Chen
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Article
| Open AccessNoninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis
Modulation of the cholinergic pathway and spleen function can reduce inflammation with invasive implants. Here, the authors show that non-invasive ultrasound stimulation of the spleen reduces disease severity in a mouse model of inflammatory arthritis, partly via altering B and T cell function.
- Daniel P. Zachs
- , Sarah J. Offutt
- & Hubert H. Lim
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Article
| Open AccessMicroglia are an essential component of the neuroprotective scar that forms after spinal cord injury
The role of microglia following spinal cord injury is not fully understood. Here, using transgenic approaches to selectively label microglia and not macrophages in mice, the authors show that microglia are highly active and accumulate at the edge of the lesion in the first weeks post injury, and also that inhibiting microglia activation impairs recovery in the early stages after spinal cord injury.
- Victor Bellver-Landete
- , Floriane Bretheau
- & Steve Lacroix
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Article
| Open AccessPD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model
Blocking the PD-1 pathway was shown to be effective in amyloid beta mouse models, yet little is known about its therapeutic potential in models of tauopathy. The authors show here that blocking PD-L1, a PD-1 ligand, is similarly effective, and that both treatments reversed cognitive deficiencies, and modified disease pathology not only in an animal model of AD, but also in the DM-hTAU mouse tauopathy model, through a mechanism that involves monocyte-derived macrophages.
- Neta Rosenzweig
- , Raz Dvir-Szternfeld
- & Michal Schwartz
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Article
| Open AccessNeuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells
Lymphangiogenesis occurs in the context of systemic inflammation and development but has not been reported for the lymphatics that surround the CNS. Here the authors show that in the context of experimental autoimmune encephatlitis, lymphangiogenesis occurs at the cribriform plate, but not the meninges, and contributes to immune cell and antigen drainage.
- Martin Hsu
- , Aditya Rayasam
- & Zsuzsanna Fabry
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Article
| Open AccessChi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation
Chitinase 3-like-3 (Chi3l3) is expressed in microglia, but its function is not clear. Here the authors show that Chi3l3 is expressed in the subventricular zone in mouse experimental immune encephalitis, which induces oligodendrogenesis.
- Sarah C. Starossom
- , Juliana Campo Garcia
- & Samia J. Khoury
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Article
| Open AccessEngrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge
Irradiation depletes brain microglia cells and induces replenishment of the pool by bone marrow (BM)-derived macrophage. Here the authors show, using mouse BM chimera, that BM-derived macrophages establish long-term residency in the brain, but remain distinct from resident microglia in their transcriptome and gene accessibility landscape.
- Anat Shemer
- , Jonathan Grozovski
- & Steffen Jung
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Article
| Open AccessCompetitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
Brain microglial cells can be replenished by blood-derived monocytes, but many aspects of this repopulation remain unclear. Here the authors show that the brain microglial niche can be replaced both by proliferating, residential microglia as well as differentiated Ly6Chi monocytes, with the latter having overlapping but distinct characteristics.
- Harald Lund
- , Melanie Pieber
- & Robert A. Harris
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Article
| Open AccessTissue-resident memory T cells populate the human brain
Tissue-resident immune cells are important for local protections from pathogens. Here the authors show that brain tissue-resident memory T cells (TRM cells) can be further subsetted by CD103 expression, with higher CD103 correlates with increased chemokine receptor and exhaustion markers such as PD1 or CTLA4, but reduced differentiation markers.
- Joost Smolders
- , Kirstin M. Heutinck
- & Jörg Hamann
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Article
| Open AccessAcute microglia ablation induces neurodegeneration in the somatosensory system
Previous studies have shown that depletion of microglia at early developmental stages leads to neuronal death. Here the authors use an inducible system to ablate microglia in adulthood, showing that such depletion leads to ataxia-like behavior and neuronal loss, and identifying the inflammatory components that may contribute.
- Stephen J. Rubino
- , Lior Mayo
- & Howard L. Weiner