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

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

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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 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 MOG35-55 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±0.14 vs 2.6±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±207 μm2-/s vs 1310±175 μm2-/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.

Original languageEnglish (US)
Article numbere47379
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 15 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Gresle, M. M., Alexandrou, E., Wu, Q., Egan, G., Jokubaitis, V., Ayers, M., Jonas, A., Doherty, W., Friedhuber, A., Shaw, G., Sendtner, M., Emery, B., Kilpatrick, T., & Butzkueven, H. (2012). Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism. PloS one, 7(10), [e47379]. https://doi.org/10.1371/journal.pone.0047379