Abstract
Abstract Activation of the NLRP3 inflammasome results in caspase-1 dependent processing and secretion of IL-1β. Inflammasome activation and IL-1β maturation is thought to require two signals: Signal I leads to transcriptional up-regulation of inflammasome components and pro-IL-1β. Various agents such as ATP and nigericin can function as signal II to activate the NLRP3 inflammasome through a mechanism that is thought to involve disrupted ion homeostasis. This in turn leads to IL-1β processing and release, as well as pyroptotic cell death. Notably, the execution of another cell death program, necroptosis, also involves cellular membrane disruption and ion flux, through the action of the protein MLKL. Here, we demonstrate that the execution of necroptosis by MLKL can lead to NLRP3 inflammasome activation and the secretion of bioactive IL-1β. We further show that IL-1β processing is independent from the cell death function of MLKL. This mechanism represents a novel inflammatory signal emanating from necroptotic cells, as well as an unexpected mechanistic cross-talk between necroptosis and inflammasome activation.
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