The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

Abstract

There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management.

Keywords: Caspase-1; Chronic traumatic encephalopathy; Concussion; Cytokine; IL-18; IL-1β; Microglia; Mild traumatic brain injury; Neuroinflammation; TBI.

Fig. 1

Formation of the NLRP3 inflammasome. Activation of the NLRP3 inflammasome involves the constituent molecules of the NLRP3 inflammasome (i.e. NLRP3, ASC and caspase-1) binding to form a complete NLRP3 inflammasome complex. This inflammasome complex allows the cleavage of pro-caspase-1 into its active isomer, caspase-1, which in turn cleaves pro-IL-1β and pro-IL-18 to their active isomers IL-1β and IL-18 respectively. The increase in these pro-inflammatory proteins ultimately leads to pyroptosis

Fig. 2

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.