The NLRP3 inflammasome in health and disease: the good, the bad and the ugly

Abstract

While interleukin (IL)-1β plays an important role in combating the invading pathogen as part of the innate immune response, its dysregulation is responsible for a number of autoinflammatory disorders. Large IL-1β activating platforms, known as inflammasomes, can assemble in response to the detection of endogenous host and pathogen-associated danger molecules. Formation of these protein complexes results in the autocatalysis and activation of caspase-1, which processes precursor IL-1β into its secreted biologically active form. Inflammasome and IL-1β activity is required to efficiently control viral, bacterial and fungal pathogen infections. Conversely, excess IL-1β activity contributes to human disease, and its inhibition has proved therapeutically beneficial in the treatment of a spectrum of serious, yet relatively rare, heritable inflammasomopathies. Recently, inflammasome function has been implicated in more common human conditions, such as gout, type II diabetes and cancer. This raises the possibility that anti-IL-1 therapeutics may have broader applications than anticipated previously, and may be utilized across diverse disease states that are linked insidiously through unwanted or heightened inflammasome activity.

Fig. 1

Structure of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. NLRP3 activation leads to homotypic interactions between the NLRP3 and apoptosis speck protein (ASC) pyrin domains and complex oligomerization. The caspase activation and recruitment domain (CARD) domains of ASC and caspase-1 interact and caspase-1 dimerization results in proximity-induced autoactivation and generation of the active tetrameric caspase-1 p20 and p10 fragments.

Fig. 2

Models for nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation. Cells, typically macrophages or dendritic cells, must first be ‘primed’ by an appropriate nuclear factor kappa B (NF-κB) transcription factor activating stimuli to induce precursor interleukin (IL)-1β expression. This often occurs by activation of a Toll-like receptor (TLR) family member (depicted), tumour necrosis factor (TNF) receptor activation, or even IL-1R activation (not depicted). NLRP3 stimulants all induce K⁺ efflux. Although this is essential for NLRP3 activity, why and how this occurs remains a mystery. Pore-forming toxins and cell permeable NLRP3 activators can also result in mitochondrial reactive oxygen species (ROS) production that may amplify or induce NLRP3 activity, possibly via an undetermined intermediate (protein X). Particulate or crystalline matter is phagocytosed and leads to endosomal/lysosomal damage, resulting in the activation/release of lysosomal proteases (i.e. cathepsins) that can cause NLRP3 induced caspase-1 activity, which may also depend on mitochondrial ROS induction and/or processing of a NLRP3 inhibitory or activating ligand.