NLRP3 (Nalp3, cryopyrin) forms an inflammasome with ASC and caspase-1 (Agostini et al, 2004) and has been the most extensively studied NLR member due to a wide array of activators of microbial and non-microbial origin (Fig 3). The NLRP3 inflammasome has been implicated in sensing a plethora of pathogenic bacteria including S. aureus and E. coli (Rathinam et al, 2012), viral pathogens such as Influenza A virus (Allen et al, 2009; Thomas et al, 2009) or vesicular stomatitis virus (Rajan et al, 2011) and the fungal pathogens Candida albicans (Gross et al, 2009) and Aspergillus fumigatus (Said-Sadier et al, 2010). Also parasites, such as Schistosoma mansoni (Ritter et al, 2010) or Dermatophagoides pteronyssinus (Dai et al, 2011) have been shown to activate NLRP3 (for a comprehensive list of NLRP3 activating pathogens please refer to Bauernfeind et al, 2011a; Franchi et al, 2012b; Lamkanfi & Dixit, 2009a). Further effort to identify NLRP3 activating compounds of pathogens revealed that several membrane pore forming or ionophoric agents of bacteria (e.g. LLO or Nigericin (Mariathasan et al, 2006), Streptolysin (Harder et al, 2009)) or viruses (M2 channel of Influenza A virus (Ichinohe et al, 2010)) activate NLRP3. Additionally, endogenous DAMPs such as extracellular ATP, gout associated uric acid crystals (Martinon et al, 2006), fibrillar amyloid beta (Halle et al, 2008) or cholesterol crystals (Duewell et al, 2010), and also environmental products like silica crystals (Hornung et al, 2008), asbestos fibers (Dostert et al, 2008) and nanomaterials (Yazdi et al, 2010) have been shown to give rise to NLRP3 inflammasome activation. The wide and structurally diverse array of agents inducing NLRP3 activation implies that a shared, but yet unknown mechanism upstream of NLRP3 enables its oligomerization. In line with this hypothesis, it was suggested that NLRP3 could monitor a host-derived DAMP that is produced or released as a consequence of cellular injury of microbial or non-microbial NLRP3 activators (Lamkanfi & Dixit, 2009b). However, there is yet no evidence for the binding of a specific ligand, serving as a common denominator, to the LRR domain of NLRP3. Despite unclear upstream mechanisms, NLRP3 is expressed at limiting levels in macrophages or dendritic cells, possibly to avoid unintended inflammation, and requires a PRR-dependent priming signal via TLRs as a first necessity for its subsequent activation (Bauernfeind et al, 2009; Juliana et al, 2012). A number of putative mechanisms have been postulated to account for the activation step, which includes phagolysosomal destabilization, generation of ROS or the induction of transmembrane ion fluxes.
Figure 3. Mechanisms resulting in NLRP3 activation. Transcription of IL-1β and NLRP3, which expression is critical, is induced by TLR signalling. At the same time, NLRP3 can be primed by a TLR-dependent,but transcription-independent signalling event. Various stimuli can activate NLRP3 that is believed to be present in an auto-inhibited state. Activated NLRP3 presumably forms multiprotein aggregates with the adaptor protein ASC and recruits caspase-1. Autocatalytically activated caspase-1 in turn processes pro-IL-1β to an active and secretable form. A plausible common downstream mechanism or signalling mediator that integrates the various processes induced by a plethora of canonical NLRP3 stimuli has not been identified but various models including as ROS production or Ca2+ release from the endoplasmatic reticulum were proposed. In contrast to these stimuli, non-canonical stimuli such as live gram-negative bacteria additionally require caspase-11 for full caspase-1 activation. The activity of caspase-11 is transcriptionally regulated by type I IFN signalling that is simultaneously engaged by bacterial compounds via TLR activation. The molecular mechanisms linking caspase-11 to caspase-1 have not been entirely identified.
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