Locatelli, G. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nature Neurosci. 543-550

Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
Nature Neuroscience (Impact Factor: 16.1). 02/2012; 15(4):543-50. DOI: 10.1038/nn.3062
Source: PubMed


Anti-myelin immunity is commonly thought to drive multiple sclerosis, yet the initial trigger of this autoreactivity remains elusive. One of the proposed factors for initiating this disease is the primary death of oligodendrocytes. To specifically test such oligodendrocyte death as a trigger for anti-CNS immunity, we inducibly killed oligodendrocytes in an in vivo mouse model. Strong microglia-macrophage activation followed oligodendrocyte death, and myelin components in draining lymph nodes made CNS antigens available to lymphocytes. However, even conditions favoring autoimmunity-bystander activation, removal of regulatory T cells, presence of myelin-reactive T cells and application of demyelinating antibodies-did not result in the development of CNS inflammation after oligodendrocyte death. In addition, this lack of reactivity was not mediated by enhanced myelin-specific tolerance. Thus, in contrast with previously reported impairments of oligodendrocyte physiology, diffuse oligodendrocyte death alone or in conjunction with immune activation does not trigger anti-CNS immunity.

1 Follower
32 Reads
  • Source
    • "Transmission electron microscopy was performed as previously described (Locatelli et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the importance of reactive astrocytes during CNS pathology is well established, the function of astroglia in adult CNS homeostasis is less well understood. With the use of conditional, astrocyte-restricted protein synthesis termination, we found that selective paralysis of GFAP(+) astrocytes in vivo led to rapid neuronal cell loss and severe motor deficits. This occurred while structural astroglial support still persisted and in the absence of any major microvascular damage. Whereas loss of astrocyte function did lead to microglial activation, this had no impact on the neuronal loss and clinical decline. Neuronal injury was caused by oxidative stress resulting from the reduced redox scavenging capability of dysfunctional astrocytes and could be prevented by the in vivo treatment with scavengers of reactive oxygen and nitrogen species (ROS/RNS). Our results suggest that the subpopulation of GFAP(+) astrocytes maintain neuronal health by controlling redox homeostasis in the adult CNS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(9). DOI:10.1016/j.celrep.2015.07.051 · 8.36 Impact Factor
  • Source
    • "Alternatively, there are underlying signals from degenerating neurons and axons that cause T cell infiltration , which are therefore due to secondary axonal loss in myelin mutant mice. Among different models, the variability of axonal involvement differs and perturbations of myelin function (in Plp1 transgenic mice) may be more detrimental to axon survival than transient demyelination induced by diphtheria toxin ( Traka et al., 2010 ; Pohl et al., 2011 ; Locatelli et al., 2012 ). We note that, in contrast to oligodendrocytes, that the genetic ablation of adult hippocampal neurons in transgenic mice with an inducible diphtheria toxin gene causes significant infiltration of T cells ( Agarwal et al., 2012 ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Myelinating cells wrap axons with multilayered myelin sheaths for rapid impulse propagation. Dysfunctions of oligodendrocytes or Schwann cells are often associated with neuroinflammation, as observed in animal models of leukodystrophies and peripheral neuropathies, respectively. The neuroinflammatory response modulates the pathological changes, including demyelination and axonal injury, but also remyelination and repair. Here we discuss different immune mechanisms as well as factors released or exposed by myelinating glia in disease conditions. The spectrum of inflammatory mediators varies with different myelin disorders and has a major impact on the beneficial or detrimental role of immune cells in nervous system integrity.
    Biological Chemistry 08/2013; 394(12). DOI:10.1515/hsz-2013-0219 · 3.27 Impact Factor
  • Source
    • "Following diphtheria toxin administration in the adult animals, acute mature oligodendrocyte loss occurred and was followed by severe secondary axonal damage in all three genetically modified mouse lines. The resulted axonal damage was not attributable to excessive CNS inflammatory responses, given that there was only mild astrocyte and microglia activation and no peripheral immune cell infiltration was observed (Buch et al., 2005; Locatelli et al., 2012). These observations are in line with the hypothesis that oligodendrocytes can support their associated axons and maintain long-term functional integrity through mechanisms other than myelination (Nave, 2010a, 2010b; Nave and Trapp, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oligodendrocyte is a highly specialized glial cell type in the vertebrate central nervous system, which guarantees the long-distance transmission of action potential by producing myelin sheath wrapping adjacent axons. Disrupted myelin and oligodendrocytes are hallmarks of some devastating neurological diseases, such as multiple sclerosis, although their contribution to neurodegeneration in a given disease is still controversial. However, accumulating evidence from clinical studies and genetic animal models implicates oligodendrocyte dysfunction as one of major events in the processes of initiation and progression of neurodegeneration. In this article, we will review recent progress in understanding non-traditional function of oligodendrocytes in neuronal support and protection independent of myelin sheath and its possible contribution to neurodegeneration. Oligodendrocytes play a pivotal role in neurodegenerative diseases among which special emphasis is given to multiple system atrophy and Alzheimer's disease in this review.
    04/2013; 8(2). DOI:10.1007/s11515-013-1260-4
Show more