Nonactivated microglia promote oligodendrocyte precursor survival and maturation through the transcription factor NF-kappa B.
We demonstrate a role for nonactivated rat microglia in the survival and maturation of oligodendrocyte precursor cells (OPCs). Media conditioned by nonactivated microglia increase the number of surviving galactocerebroside(+) (GalC(+)) oligodendrocytes in vitro at 48 h by inhibiting the apoptosis of OPCs and stimulating their maturation to GalC+ oligodendrocytes. These effects are not observed with medium conditioned by microglia activated with interferon-gamma (IFN-gamma). Conditioned medium from nonactivated microglia is associated with upregulation in OPCs of nuclear factor of kappa binding (NF-kappa B) p65 subunit. The use of antisense to the inhibitor of kappa binding (I kappa B) induces p65 subunit activation in OPCs and, in common with medium conditioned by nonactivated microglia, also inhibits OPC apoptosis and promotes cell maturation. Anti-platelet-derived growth factor (PDGF) antibody abolishes this effect even though PDGF-A chain is expressed at similar levels within both nonactivated and IFN-gamma-activated microglia and both conditioned media have similar levels of PDGF-A chain bioactivity. However, only conditioned medium from nonactivated microglia recruit phosphatidyl-3-inositol (PI-3) kinase to the PDGF-alpha receptor and synergise with endogenous PDGF-A chain to increase NF-kappa B activation. These results suggest that, dependent on their state of activation, microglia produce soluble factors that promote oligodendrocyte development through an effect on the PDGF-alpha receptor-signalling pathway.
University of Cambridge Neurology unit, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK.
R S
RS
Nicholas
M G
MG
Wing
A
A
Compston
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000187:drug effects / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D000906:Antibodies; D016375:Antisense Elements (Genetics); D017077:Culture Media, Conditioned; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D007371:Interferon-gamma; D020796:Receptor, Platelet-Derived Growth Factor alpha