Potential NLRP3 inflammasome priming and activation 1 following TBI. TBI is known to induce an array of molecular changes that may trigger the two-step activation of the NLRP3 inflammasome. (1) Priming of the inflammasome induces transcriptional up-regulation of NLRP3 and pro-IL-1β as well as post-translational modifications of the NLRP3 protein. The most commonly investigated priming signals in the context of sterile trauma is the recognition of DAMPs to induce TLR-NF-κB signalling. DAMPs such as ROS, HMGB1, extracellular matrix molecules and heat shock proteins are known to prime the NLRP3 inflammasome and have also been shown to be up-regulated following TBI. (2) Activation of the inflammasome occurs following priming, and involves the formation of the NLRP3 inflammasome from its constituent proteins (NLRP3, ASC and caspase-1). TBI features a range of endogenous changes that can serve as activating signals, including but not limited to: ionic changes such as potassium and chloride efflux, sodium and calcium efflux, altered calcium signalling, lysosomal destabilisation and products of mitochondrial dysfunction such as mitochondrial DNA and ROS. Importantly, some signals have been shown to upregulate both priming and activation of the NLRP3 inflammasome. This complete inflammasome complex ultimately results in the release of IL-1β.