Fig. 8

Schematic diagram of proposed interactions between XIAP and the inflammasome cascade. In our previous animal studies, the inflammasome can be activated by either amyloid beta (Aβ) or membrane attack complex (MAC). Inhibition of either the NF-κB pathway (by vinpocetine) or the MAC deposition (by ATAC) is sufficient to prevent inflammasome activation. Reduced XIAP protein levels are found both in vitro (by LLOMe-mediated lysosomal destabilization) and in vivo (as shown in Fig. 1) upon inflammasome activation and can be reversed by ATAC (the “activating” step), not vinpocetine (the “priming” step). Inhibition of Caspase-1 cleavage by YVAD also reduced the cleavage of XIAP and IL-1β secretion. When RPE cells have reduced XIAP (e.g., silenced by siRNA interference) prior to the activation of inflammasome, more IL-18 and IL-1β will be secreted. However, if XIAP is adequate (e.g., overexpressed by plasmid transfection), a lower level of IL-1β secretion is observed