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Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism

Please always quote using this URN: urn:nbn:de:bvb:20-opus-134617
  • Leukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination ofLeukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG\(_{35-55}\) EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1\(\pm\)0.14 vs 2.6\(\pm\)0.19; P<0.05). These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540\(\pm\)207 \(\mu\)m\(^2\)-/s vs 1310\(\pm\)175 \(\mu\)m\(^2\)-/s; P<0.05), and optic nerve (-12.5%) and spinal cord (-16%) axon densities; and increased serum neurofilament-H levels (2.5 fold increase). No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism.show moreshow less

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Metadaten
Author: Melissa M. Gresle, Estella Alexandrou, Qizhu Wu, Gary Egan, Vilija Jokubaitis, Margaret Ayers, Anna Jonas, William Doherty, Anna Friedhuber, Gerry Shaw, Michael Sendtner, Ben Emery, Trevor Kilpatrick, Helmut Butzkueven
URN:urn:nbn:de:bvb:20-opus-134617
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Klinische Neurobiologie
Language:English
Parent Title (English):PLoS One
Year of Completion:2012
Volume:7
Issue:10
Pagenumber:e47379
Source:PLoS ONE 7(10): e47379. doi:10.1371/journal.pone.0047379
DOI:https://doi.org/10.1371/journal.pone.0047379
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:ciliary neurotrophic factor; degeneration; demyelination; factor prevents; injury; motoneurons; mulitple-sclerosis patients; neurons; receptor; survival
Release Date:2017/11/09
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung