Richard M Ransohoff

Biogen Idec, Уэстон, Massachusetts, United States

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Publications (393)3125.55 Total impact

  • [Show abstract] [Hide abstract]
    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. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Neurology 04/2015; 14(4):388-405. DOI:10.1016/S1474-4422(15)70016-5 · 21.82 Impact Factor
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    ABSTRACT: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics. © 2015 Jay et al.
    Journal of Experimental Medicine 03/2015; 212(3). DOI:10.1084/jem.20142322 · 13.91 Impact Factor
  • Richard M Ransohoff, David A Hafler, Claudia F Lucchinetti
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    ABSTRACT: Multiple sclerosis (MS) has been thought to be a complex and indecipherable disease, and poorly understood with regards to aetiology. Here, we suggest an emphatically positive view of progress over several decades in the understanding and treatment of MS, particularly focusing on advances made within the past 20 years. As with virtually all complex disorders, MS is caused by the interaction of genetic and environmental factors. In recent years, formidable biochemical, bioinformatic, epidemiological and neuroimaging tools have been brought to bear on research into the causes of MS. While susceptibility to the disease is now relatively well accounted for, disease course is not and remains a salient challenge. In the therapeutic realm, numerous agents have become available, reflecting the fact that the disease can be attacked successfully at many levels and using varied strategies. Tailoring therapies to individuals, risk mitigation and selection of first-line as compared with second-line medications remain to be completed. In our view, the MS landscape has been comprehensively and irreversibly transformed by this progress. Here we focus on MS therapeutics-the most meaningful outcome of research efforts.
    Nature Reviews Neurology 02/2015; DOI:10.1038/nrneurol.2015.14 · 15.52 Impact Factor
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    Richard M Ransohoff
    12/2014; 1(4):e44. DOI:10.1212/NXI.0000000000000044
  • Richard M Ransohoff
    Science 10/2014; 346(6205):36-7. DOI:10.1126/science.1260705 · 31.48 Impact Factor
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    Richard M Ransohoff
    10/2014; 1(3):e37. DOI:10.1212/NXI.0000000000000037
  • Atsuko Katsumoto, Haiyan Lu, Aline S Miranda, Richard M Ransohoff
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    ABSTRACT: Microglia, the only nonneuroepithelial cells found in the parenchyma of the CNS, originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5-10 in mice). Thereafter, microglia are maintained independently of any input from the blood and, in particular, do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions. In this article, we discuss the physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology.
    The Journal of Immunology 09/2014; 193(6):2615-2621. DOI:10.4049/jimmunol.1400716 · 5.36 Impact Factor
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    ABSTRACT: Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD-extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)-remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2014; 34(37):12538-46. DOI:10.1523/JNEUROSCI.0853-14.2014 · 6.75 Impact Factor
  • Cristina Limatola, Richard M Ransohoff
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    ABSTRACT: Since the initial cloning of fractalkine/CX3CL1, it was proposed that the only known member of the CX3C or δ subfamily of chemotactic cytokines could play some significant role in the nervous system, due to its high expression on neurons. The pivotal description of the localization of the unique CX3CL1 receptor, CX3CR1, on microglial cells, firmed up by the generation of cx3cr1(GFP/GFP) mice, opened the road to the hypothesis of some specific key interactions between microglia and neurons mediated by this pair. This expectation has been indeed supported by recent exciting evidence indicating that CX3CL1-mediated microglia-neuron interaction modulates basic physiological activities during development, adulthood and aging, including: synaptic pruning; promoting survival of neurons and neural precursors; modulating synaptic transmission and plasticity; enhancing synapse and network maturation; and facilitating the establishment of neuropathic pain circuits. Beyond playing such fascinating roles in physiological conditions, CX3CL1 signaling has been implicated in different neuropathologies. Early papers demonstrated that the levels of CX3CL1 may be modulated by various toxic stimuli in vitro and that CX3CL1 signaling is positively or negatively regulated in EAE and MS, in HIV infection and LPS challenge, in epilepsy, in brain tumors, and in other neuropathologies. In this review we focus on the experimental evidence of CX3CL1 involvement in neuroprotection and survey the common molecular and cellular mechanisms described in different brain diseases.
    Frontiers in Cellular Neuroscience 08/2014; 8:229. DOI:10.3389/fncel.2014.00229 · 4.18 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    Richard M Ransohoff
    08/2014; 1(2):e23. DOI:10.1212/NXI.0000000000000023
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    ABSTRACT: Leukocyte transendothelial migration (TEM; diapedesis) is a critical event in immune surveillance and inflammation. Most TEM occurs at endothelial cell borders (paracellular). However, there is indirect evidence to suggest that, at the tight junctions of the blood-brain barrier (BBB), leukocytes migrate directly through the endothelial cell body (transcellular). Why leukocytes migrate through the endothelial cell body rather than the cell borders is unknown. To test the hypothesis that the tightness of endothelial cell junctions influences the pathway of diapedesis, we developed an in vitro model of the BBB that possessed 10-fold higher electrical resistance than standard culture conditions and strongly expressed the BBB tight junction proteins claudin-5 and claudin-3. We found that paracellular TEM was still the predominant pathway (≥98%) and TEM was dependent on PECAM-1 and CD99. We show that endothelial tight junctions expressing claudin-5 are dynamic and undergo rapid remodeling during TEM. Membrane from the endothelial lateral border recycling compartment is mobilized to the exact site of tight junction remodeling. This preserves the endothelial barrier by sealing the intercellular gaps with membrane and engaging the migrating leukocyte with unligated adhesion molecules (PECAM-1 and CD99) as it crosses the cell border. These findings provide new insights into leukocyte-endothelial interactions at the BBB and suggest that tight junctions are more dynamic than previously appreciated.
    The Journal of Immunology 07/2014; 193(5). DOI:10.4049/jimmunol.1400700 · 5.36 Impact Factor
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    ABSTRACT: In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
    Journal of Experimental Medicine 07/2014; 211(8). DOI:10.1084/jem.20132477 · 13.91 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P876-P877. DOI:10.1016/j.jalz.2014.07.019 · 17.47 Impact Factor
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    ABSTRACT: Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na(+) channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.
    Proceedings of the National Academy of Sciences 06/2014; 111(27). DOI:10.1073/pnas.1401155111 · 9.81 Impact Factor
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    Richard M Ransohoff
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    ABSTRACT: In vitro blood-brain barrier (BBB) models can be useful for understanding leukocyte-endothelial interactions at this unique vascular-tissue interface. Desirable features of such a model include shear stress, non-transformed cells and co-cultures of brain microvascular endothelial cells with astrocytes. Recovery of transmigrated leukocytes for further analysis is also appealing.
    Journal of Neuroscience Methods 05/2014; DOI:10.1016/j.jneumeth.2014.05.013 · 1.96 Impact Factor
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    ABSTRACT: Aminoglycoside antibiotics are highly effective agents against gram-negative bacterial infections, but they cause adverse effects on hearing and balance dysfunction as a result of toxicity to hair cells of the cochlea and vestibular organs. While ototoxicity has been comprehensively studied, the contributions of the immune system, which controls the host response to infection, have not been studied in antibiotic ototoxicity. Recently, it has been shown that an inflammatory response is induced by hair cell injury. In this study, we found that lipopolysaccharide (LPS), an important component of bacterial endotoxin, when given in combination with kanamycin and furosemide, augmented the inflammatory response to hair cell injury and exacerbated hearing loss and hair cell injury. LPS injected into the peritoneum of experimental mice induced a brisk cochlear inflammatory response with recruitment of mononuclear phagocytes into the spiral ligament, even in the absence of ototoxic agents. While LPS alone did not affect hearing, animals that received LPS prior to ototoxic agents had worse hearing loss compared to those that did not receive LPS pretreatment. The poorer hearing outcome in LPS-treated mice did not correlate to changes in endocochlear potential. However, LPS-treated mice demonstrated an increased number of CCR2(+) inflammatory monocytes in the inner ear when compared with mice treated with ototoxic agents alone. We conclude that LPS and its associated inflammatory response are harmful to the inner ear when coupled with ototoxic medications and that the immune system may contribute to the final hearing outcome in subjects treated with ototoxic agents.
    Journal of the Association for Research in Otolaryngology 05/2014; DOI:10.1007/s10162-014-0458-8 · 2.55 Impact Factor
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    Journal of Experimental Medicine 05/2014; 211(5):1003. DOI:10.1084/jem.2013131404222014c · 13.91 Impact Factor
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    ABSTRACT: After traumatic spinal cord injury, functional deficits increase as axons die back from the center of the lesion and the glial scar forms. Axonal die back occurs in two phases: an initial axon intrinsic stage that occurs over the first several hours and a secondary phase which takes place over the first few weeks after injury. Here, we examine the secondary phase, which is marked by infiltration of macrophages. Using powerful time lapse multi-photon imaging, we captured images of interactions between Cx3cr1(+/GFP) macrophages and microglia and Thy-1(YFP) axons in a mouse dorsal column crush spinal cord injury model. Over the first few weeks after injury, axonal retraction bulbs within the lesion are static except when axonal fragments are lost by a blebbing mechanism in response to physical contact followed by phagocytosis by mobile Cx3Cr1(+/GFP) cells. Utilizing a radiation chimera model to distinguish marrow-derived cells from radio-resistant CNS resident microglia, we determined that the vast majority of accumulated cells in the lesion are derived from the blood and only these are associated with axonal damage. Interestingly, CNS-resident Cx3Cr1(+/GFP)microglia did not increasingly accumulate nor participate in neuronal destruction in the lesion during this time period. Additionally, we found that the blood-derived cells consisted mainly of singly labeled Ccr2(+/RFP)macrophages, singly labeled Cx3Cr1(+/GFP)macrophages and a small population of double-labeled cells. Since all axon destructive events were seen in contact with a Cx3Cr1(+/GFP)cell, we infer that the CCR2 single positive subset is likely not robustly involved in axonal dieback. Finally, in our model, deletion of CCR2, a chemokine receptor, did not alter the position of axons after dieback. Understanding the in vivo cellular interactions involved in secondary axonal injury may lead to clinical treatment candidates involving modulation of destructive infiltrating blood monocytes.
    Experimental Neurology 01/2014; DOI:10.1016/j.expneurol.2014.01.013 · 4.62 Impact Factor
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    ABSTRACT: Background:In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.Methods:We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro.Results:CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.Conclusions:These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.British Journal of Cancer advance online publication, 14 January 2014; doi:10.1038/bjc.2013.830
    British Journal of Cancer 01/2014; 110(5). DOI:10.1038/bjc.2013.830 · 5.08 Impact Factor

Publication Stats

24k Citations
3,125.55 Total Impact Points


  • 2015
    • Biogen Idec
      Уэстон, Massachusetts, United States
  • 1998–2014
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 1994–2014
    • Case Western Reserve University
      • Department of Molecular Medicine
      Cleveland, Ohio, United States
  • 1989–2014
    • Cleveland Clinic
      • • Department of Immunology
      • • Department of Neurosciences
      • • Department of Pathobiology
      • • Department of Neuroradiology
      Cleveland, Ohio, United States
    • Cleveland Medical Devices Inc.
      Cleveland, Ohio, United States
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 2013
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
  • 2010–2013
    • Barrow Neurological Institute
      • Department of Neurology
      Phoenix, Arizona, United States
  • 2012
    • Osaka University
      • Experimental Immunology Group
      Ibaraki, Osaka-fu, Japan
  • 2011
    • Mayo Clinic - Rochester
      • Department of Neurology
      Rochester, MN, United States
  • 2008–2010
    • University of Southern California
      • Department of Pathology
      Los Angeles, California, United States
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2009
    • Rowe Neuroscience Institute
      Lenexa, Kansas, United States
  • 2006
    • Brown University
      • Department of Molecular Microbiology and Immunology
      Providence, Rhode Island, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
  • 2005
    • University of California, Berkeley
      Berkeley, California, United States
  • 1997–2005
    • University of Lodz
      • Department of Neurobiology
      Łódź, Łódź Voivodeship, Poland
  • 2000–2003
    • Johns Hopkins University
      • Department of Neurology
      Baltimore, Maryland, United States
  • 2002
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 1996–1997
    • University of Alabama at Birmingham
      • Department of Cell, Developmental and Integrative Biology (CDIB)
      Birmingham, AL, United States
    • Bristol-Myers Squibb
      • Department of Experimental Pathology
      New York, New York, United States