LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival.
Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.
Butzkueven
Helmut
H
The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Victoria, Australia.
Zhang
Jian-Guo
JG
Soilu-Hanninen
Merja
M
Hochrein
Hubertus
H
Chionh
Fiona
F
Shipham
Kylie A
KA
Emery
Ben
B
Turnley
Ann M
AM
Petratos
Steven
S
Ernst
Matthias
M
Bartlett
Perry F
PF
Kilpatrick
Trevor J
TJ
D000595:Amino Acid Sequence; D000818:Animals; D002470:Cell Survival; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009836:Oligodendroglia / Q000166:cytology* / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D018121:Receptors, Cytokine / Q000502:physiology*; D053606:Receptors, OSM-LIF; D015398:Signal Transduction
D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D010446:Peptide Fragments; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF