Granulosa cell subtypes respond by autophagy or cell death to oxLDL-dependent activation of the oxidized lipoprotein receptor 1 and toll-like 4 receptor.
Autophagic cell death has been observed in granulosa cell cultures via the oxLDL-dependent activation of lectin-like oxidized low density lipoprotein receptor 1 (LOX-1). This activation might differ for cytokeratin-positive (CK(+)) and CK(-) granulosa cells. In particular, LOX-1 and toll-like receptor 4 (TLR4), one of the pattern recognition receptors of innate immunity, might be diversely regulated. Granulosa cell subtype cultures were established from the follicle harvests of patients undergoing in vitro fertilization (IVF) therapy. In response to oxLDL treatment, the fibroblast-like CK(-) cells upregulated LOX-1 and exhibited reparative autophagy, which could be blocked with anti-LOX-1 antibody. The epithelioid-like CK(+) cells did not regulate LOX-1 expression upon oxLDL application, but the expression of TLR4 and CD14 increased between 0 and 36 h of oxLDL/nDL treatment. This upregulation was associated with nonapoptotic cell death based on the absence of cleaved caspase-3. Reactive oxygen species (ROS) increased with 12 h oxLDL application and steroidogenic acute regulatory (StAR) protein expression was negligible. In CK(-) cells, the inhibition of TLR4 downregulated LOX-1 and induced apoptosis. We concluded that CK(-) granulosa cells are protected against oxLDL-dependent apoptosis by TLR4, whereas, in CK(+) cells, oxLDL-induced TLR4 activation triggers nonapoptotic cell death. The CK(+) cells might represent immune-like granulosa cells involved in ovarian remodeling processes.
Serke
Heike
H
Institute of Anatomy, University of Leipzig, Leipzig, Germany.
Vilser
Constanze
C
Nowicki
Marcin
M
Hmeidan
Fayez A
FA
Blumenauer
Verona
V
Hummitzsch
Katja
K
Lösche
Andreas
A
Spanel-Borowski
Katharina
K
D001343:Autophagy / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D007633:Keratins; D053148:Caspase 3