Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair.
Leukemia inhibitory factor (LIF) receptor signaling limits the severity of inflammatory demyelination in experimental autoimmune encephalomyelitis, a T-cell dependent animal model of multiple sclerosis (MS) [Butzkueven et al. (2002) Nat Med 8:613-619]. To identify whether LIF exerts direct effects within the central nervous system to limit demyelination, we have studied the influence of LIF upon the phenotype of mice challenged with cuprizone, a copper chelator, which produces a toxic oligodendrocytopathy. We find that exogenously administered LIF limits cuprizone-induced demyelination. Knockout mice deficient in LIF exhibit both potentiated demyelination and oligodendrocyte loss after cuprizone challenge, an effect that is ameliorated by exogenous LIF, arguing for a direct beneficial effect of endogenous LIF receptor signaling. Numbers of oligodendrocyte progenitor cells in cuprizone-challenged mice are not influenced by either exogenous LIF or LIF deficiency, arguing for effects directed to the differentiated oligodendrocyte. Studies on the influence of LIF upon remyelination after cuprizone challenge fail to reveal any significant effect of exogenous LIF. The LIF-knockout mice do, however, display impaired remyelination, although oligodendrocyte replenishment, previously identified to occur from the progenitor pool, is not significantly compromised. Thus endogenous LIF receptor signaling is not only protective of oligodendrocytes but can also enhance remyelination, and exogenous LIF has therapeutic potential in limiting the consequences of oligodendrocyte damage.
Marriott
Mark P
MP
Howard Florey Institute, The University of Melbourne, Victoria, Australia.
Emery
Ben
B
Cate
Holly S
HS
Binder
Michele D
MD
Kemper
Dennis
D
Wu
Qizhu
Q
Kolbe
Scott
S
Gordon
Ian R
IR
Wang
Hong
H
Egan
Gary
G
Murray
Simon
S
Butzkueven
Helmut
H
Kilpatrick
Trevor J
TJ
D000704:Analysis of Variance; D000818:Animals; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007211:Indoles; D053605:Leukemia Inhibitory Factor / Q000008:administration & dosage* / Q000172:deficiency / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000473:pathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009185:Myelin Proteins; C007293:DAPI; D003471:Cuprizone