Caspase-1 ablation protects photoreceptors in a model of autosomal dominant retinitis pigmentosa.

PURPOSE: 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.