Caspase-8 Potentiates Triglyceride (TG)-Induced Cell Death of THP-1 Macrophages via a Positive Feedback Loop

Hypertriglyceridemia is the main risk factor for atherosclerosis.It is reported that triglyceride (TG) induces macrophage cell death, and is involved in the formation of plaques and development of atherosclerosis.We previously reported that TG-induced cell death of macrophages is mediated via pannexin-1 activation, which increases the extracellular ATP and subsequent increase in potassium efflux, thereby activating the caspase-2/caspase-1/apoptotic caspases, including the caspase-8 pathway.Contrarily, some studies have reported that caspase-8 is an upstream molecule of caspase-1 and caspase-2 in several cellular processes.Therefore, this study was undertaken to investigate whether caspase-8 influences its upstream molecules in TG-stimulated macrophage cell death.We first confirmed that caspase-8 induces caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage in TG-treated macrophages.Next, we determined that the inhibition of caspase-8 results in reduced caspase-1 and -2 activity, which are upstream molecules of caspase-8 in TG-induced cell death of macrophages.We also found that ATP treatment restores the caspase-8 inhibitor-induced caspase-2 activity, thereby implying that caspase-8 affects the upstream molecules responsible for increasing the extracellular ATP levels in TG-induced macrophage cell death.Taken together, these findings indicate that caspase-8 potentiates the TG-induced macrophage cell death by activating its upstream molecules.