Author
Jing-Wei Zhao
Other affiliations: Chinese Academy of Sciences, Fudan University
Bio: Jing-Wei Zhao is an academic researcher from University of Cambridge. The author has contributed to research in topics: Retina & Remyelination. The author has an hindex of 16, co-authored 21 publications receiving 2544 citations. Previous affiliations of Jing-Wei Zhao include Chinese Academy of Sciences & Fudan University.
Topics: Retina, Remyelination, Cell biology, Cholinergic neuron, Apoptosis
Papers
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TL;DR: It is found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started and activin-A is identified as a therapeutic target for CNS regeneration.
Abstract: In this study, the authors show that oligodendrocyte differentiation and remyelination after a CNS lesion coincides with a switch in microglial/macrophage polarization from a pro-inflammatory, M1, phenotype to an anti-inflammatory, M2, phenotype. This M2-dependant effect was in part mediated by secretion of the TGFβ family member, Activin-A.
1,310 citations
TL;DR: It is shown that remyelination of experimentally induced demyelinating activity is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis, and that remYelination-enhancing therapies targeting endogenous cells can be effective throughout life.
547 citations
TL;DR: It is reported that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death, indicating a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagcytosis.
Abstract: It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain's macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death. Specifically, two inflammatory bacterial ligands, lipoteichoic acid or LPS (agonists of glial TLR2 and TLR4, respectively), stimulated microglial proliferation, phagocytic activity, and engulfment of ∼30% of neurons within 3 d. Phagocytosis of neurons was dependent on the microglial release of soluble mediators (and peroxynitrite in particular), which induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Surprisingly, however, eat-me signaling was reversible, so that blocking any step in a phagocytic pathway consisting of PS exposure, the PS-binding protein milk fat globule epidermal growth factor-8, and its microglial vitronectin receptor was sufficient to rescue up to 90% of neurons without reducing inflammation. Hence, our data indicate a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration, and therefore might be beneficial during brain infection, trauma, ischemia, neurodegeneration, and aging.
313 citations
TL;DR: It is shown that MFG-E8 can mediate phagocytosis of viable neurons during neuroinflammation induced by lipopolysaccharide (LPS), thereby causing neuronal death and implying that phagocytetosis actively contributes to neuronal death during brain inflammation.
Abstract: Milk-fat globule EGF factor-8 (MFG-E8, SED1, lactadherin) is known to mediate the phagocytic removal of apoptotic cells by bridging phosphatidylserine (PS)-exposing cells and the vitronectin receptor (VR) on phagocytes. However, we show here that MFG-E8 can mediate phagocytosis of viable neurons during neuroinflammation induced by lipopolysaccharide (LPS), thereby causing neuronal death. In vitro, inflammatory neuronal loss is independent of apoptotic pathways, and is inhibited by blocking the PS/MFG-E8/VR pathway (by adding PS blocking antibodies, annexin V, mutant MFG-E8 unable to bind VR, or VR antagonist). Neuronal loss is absent in Mfge8 knock-out cultures, but restored by adding recombinant MFG-E8, without affecting inflammation. In vivo, LPS-induced neuronal loss is reduced in the striatum of Mfge8 knock-out mice or by coinjection of an MFG-E8 receptor (VR) inhibitor into the rat striatum. Our data show that blocking MFG-E8-dependent phagocytosis preserves live neurons, implying that phagocytosis actively contributes to neuronal death during brain inflammation.
168 citations
TL;DR: The Cambridge Protocol is an efficient method of deriving stem-like tumour initiating cells from glioblastoma by combining neurosphere and monolayer culture techniques to improve the efficiency with which cells can be derived from clinical tumour samples under defined serum-free conditions.
149 citations
Cited by
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University Hospital Bonn1, University of California, Riverside2, Harvard University3, Case Western Reserve University4, University of Illinois at Chicago5, European Institute6, VA Palo Alto Healthcare System7, Stanford University8, Spanish National Research Council9, Cleveland Clinic Lerner Research Institute10, Hong Kong University of Science and Technology11, University of California, Los Angeles12, University of Southern Denmark13, University of Cambridge14, University of the Basque Country15, Ikerbasque16, University of Manchester17, RIKEN Brain Science Institute18, University of Eastern Finland19, University of Massachusetts Medical School20, University of Bonn21, Center of Advanced European Studies and Research22, University of Southern California23, University of South Florida24, Duke University25, Southampton General Hospital26, University of Southampton27, Moorgreen Hospital28, Louisiana State University29, Imperial College London30, Centre national de la recherche scientifique31, Karolinska Institutet32, Max Planck Society33, University of Tübingen34, University of Groningen35, University of Colorado Denver36, Douglas Mental Health University Institute37
TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
3,947 citations
TL;DR: This review discusses the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing,pro-fibrotic, anti- inflammatory, anti -fib rotic, Pro-resolving, and tissue-regenerating phenotypes after injury, and highlights how some of these mechanisms and macrophage activation states could be exploited therapeutically.
2,284 citations
TL;DR: The current understanding of multiple sclerosis immunopathology is discussed, long-standing hypotheses regarding the role of the immune system in the disease are evaluated, and key questions that are still unanswered are delineated.
Abstract: Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.
1,482 citations
TL;DR: It is found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started and activin-A is identified as a therapeutic target for CNS regeneration.
Abstract: In this study, the authors show that oligodendrocyte differentiation and remyelination after a CNS lesion coincides with a switch in microglial/macrophage polarization from a pro-inflammatory, M1, phenotype to an anti-inflammatory, M2, phenotype. This M2-dependant effect was in part mediated by secretion of the TGFβ family member, Activin-A.
1,310 citations
TL;DR: The analysis of RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers.
1,156 citations