Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis.
The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-gamma (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-alpha production, and overcame blockage of IGF-I production caused by IFN-gamma. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool.
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Oleg
O
Butovsky
Gennady
G
Landa
Gilad
G
Kunis
Yaniv
Y
Ziv
Hila
H
Avidan
Nadav
N
Greenberg
Adi
A
Schwartz
Igor
I
Smirnov
Ayala
A
Pollack
Steffen
S
Jung
Michal
M
Schwartz
D000818:Animals; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma