Caspase-1 ablation protects photoreceptors in a model of autosomal dominant retinitis pigmentosa.
OBJECTIVE
Caspase-1 gene expression has been reported to be upregulated during light-induced retinal degeneration and to be reduced after neuroprotective treatments. Thus, caspase-1 may be proapoptotic in the retina. To test directly the role of caspase-1 in photoreceptor apoptosis, three mouse models were analyzed for retinal degeneration in the presence or absence of caspase-1.


METHODS
Photoreceptor apoptosis was monitored in one model of induced (exposure to light) and in two models of inherited (rd1, VPP) retinal degeneration. Retinal degeneration was assessed qualitatively by light microscopy and quantitatively by the determination of free nucleosomes with ELISA or by rhodopsin measurements. Gene expression and protein levels were assessed by real-time RT-PCR and by Western blot analysis, respectively.


RESULTS
Levels of caspase-1 proenzyme increased in all models of retinal degeneration concomitantly with the onset of cell death. Maturation or classic activity of caspase-1 was not detected in the retina. Ablation of caspase-1 was protective in the model of adRP (VPP mouse), but not in the two other models. Ablation of interleukin-1 receptor type 1 was without effect. Expression of monocyte chemoattractant protein (MCP)-1 increased in the model protected by caspase-1 ablation.


CONCLUSIONS
Increased retinal expression of caspase-1 proenzyme may be a common marker for photoreceptor degeneration. The differential effects of caspase-1 ablation suggests a modulatory role of caspase-1 for photoreceptor apoptosis in some but not all models. Such a modulatory activity may involve a caspase-1 function different from the classic activation of interleukin-1beta.
Samardzija
Marijana
M
Laboratory for Retinal Cell Biology, Department of Ophthalmology, Center for Integrative Human Physiology (CIHP), Neuroscience Center Zürich (ZNZ), University of Zürich, Zürich, Switzerland.
Wenzel
Andreas
A
Thiersch
Markus
M
Frigg
Rico
R
Remé
Charlotte
C
Grimm
Christian
C
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020170:Caspase 1 / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005799:Genes, Dominant; D008027:Light; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D018696:Neuroprotective Agents; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology* / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000517:prevention & control; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D012160:Retina / Q000528:radiation effects; D012162:Retinal Degeneration / Q000517:prevention & control; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018696:Neuroprotective Agents; D053573:Receptors, Interleukin-1 Type I; D020170:Caspase 1