25-hydroxycholesterol provokes oligodendrocyte cell line apoptosis and stimulates the secreted phospholipase A2 type IIA via LXR beta and PXR.
In several neurodegenerative diseases of the CNS, oligodendrocytes are implicated in an inflammatory process associated with altered levels of oxysterols and inflammatory enzymes such as secreted phospholipase A2 (sPLA2). In view of the scarce literature related to this topic, we investigated oxysterol effects on these myelinating glial cells. Natural oxysterol 25-hydroxycholesterol (25-OH; 1 and 10 microM) altered oligodendrocyte cell line (158N) morphology and triggered apoptosis (75% of apoptosis after 72 h). These effects were mimicked by 22(S)-OH (1 and 10 microM) which does not activate liver X receptor (LXR) but not by a synthetic LXR ligand (T0901317). Therefore, oxysterol-induced apoptosis appears to be independent of LXR. Interestingly, sPLA2 type IIA (sPLA2-IIA) over-expression partially rescued 158N cells from oxysterol-induced apoptosis. In fact, 25-OH, 24(S)-OH, and T0901317 stimulated sPLA2-IIA promoter and sPLA2 activity in oligodendrocyte cell line. Accordingly, administration of T0901317 to mice enhanced sPLA2 activity in brain extracts by twofold. Short interfering RNA strategy allowed to establish that stimulation of sPLA2-IIA is mediated by pregnane X receptor (PXR) at high oxysterol concentration (10 microM) and by LXR beta at basal oxysterol concentration. Finally, GC coupled to mass spectrometry established that oligodendrocytes contain oxysterols and express their biosynthetic enzymes, suggesting that they may act through autocrine/paracrine mechanism. Our results show the diversity of oxysterol signalling in the CNS and highlight the positive effects of the LXR/PXR pathway which may open new perspectives in the treatment of demyelinating and neurodegenerative diseases.
Trousson
Amalia
A
UMR788, INSERM and University Paris-Sud 11, IFR 93, Le Kremlin-Bicêtre Cedex, France.
Bernard
Sophie
S
Petit
Patrice X
PX
Liere
Philippe
P
Pianos
Antoine
A
El Hadri
Khadija
K
Lobaccaro
Jean-Marc A
JM
Ghandour
M Said
MS
Raymondjean
Michel
M
Schumacher
Michael
M
Massaad
Charbel
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D008401:Gas Chromatography-Mass Spectrometry; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000071518:Liver X Receptors; D051379:Mice; D018625:Microscopy, Atomic Force; D009836:Oligodendroglia / Q000187:drug effects* / Q000648:ultrastructure; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011987:Receptors, Steroid / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D054501:Group II Phospholipases A2; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C007997:25-hydroxycholesterol