Inflammation is the host response to microbial infection or sterile injury that aims to eliminate the insult and restore homeostasis. Although it is well established that the NLRP3 inflammasome is activated by microbial products and molecules released during sterile injury, it is unclear whether the responses elicited by these different types of signals are distinct. The canonical activation of NLRP3 requires both an activation signal and an additional priming or licencing signal that triggers post-translational modifications of NLRP3 necessary for inflammasome formation. In this study, we examine priming of NLRP3 in mouse and human macrophages and observe temporal and species-specific differences in the response to NLRP3 activation when the nature and timing of the priming signal is varied. In human macrophages, simultaneous stimulation with nigericin and TLR4 or TLR1/2 ligands induces a rapid cell death response. However, extended priming via TLR4 or TLR1/2 promotes cell survival and pro-IL-1β processing following activation of NLRP3. In contrast, priming via TLR7 or TNF prior to nigericin stimulation progressively increases both cell death and IL-1β processing. These results suggest that NLRP3 integrates priming signals originating from pathogen or host-derived factors to initiate tailored responses appropriate to the nature of the stimulus. Mechanistically, signalling through TLR4 activates the PI3K-AKT axis to negatively regulate cell death. Inhibition of PI3K results in increased NLRP3-dependent cell death and IL-1β secretion in human macrophages. We therefore identify a key regulatory pathway that controls NLRP3 driven inflammation in the human immune system.