Leukemia inhibitory factor protects axons in experimental autoimmune encephalomyelitis via an oligodendrocyte-independent mechanism.
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.
Department of Medicine, The Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. mgresle@unimelb.edu.au
Melissa M
MM
Gresle
Estella
E
Alexandrou
Qizhu
Q
Wu
Gary
G
Egan
Vilija
V
Jokubaitis
Margaret
M
Ayers
Anna
A
Jonas
William
W
Doherty
Anna
A
Friedhuber
Gerry
G
Shaw
Michael
M
Sendtner
Ben
B
Emery
Trevor
T
Kilpatrick
Helmut
H
Butzkueven
D000818:Animals; D001369:Axons / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000378:metabolism; D015398:Signal Transduction
D020934:Ciliary Neurotrophic Factor; C494200:Il6st protein, mouse; D053605:Leukemia Inhibitory Factor; D050822:Cytokine Receptor gp130