Policing the cytosol--bacterial-sensing inflammasome receptors and pathways

Abstract

Pattern recognition receptors recognize signals originating from pathogens and comprise a large part of the arsenal in innate immune responses. The NOD-like receptors (NLRs) are one particular class of these receptors that survey the cytoplasm for signs of pathogen invasion. Upon detection, they trigger the formation of a macromolecular complex called the inflammasome that is required for elimination of the pathogen, as well as amplifying a pro-inflammatory response. Although the core machinery has been defined, recent data emphasize the complexity of how NLR inflammasomes function. Here, we highlight new discoveries that reveal how precisely fine-tuned NLR inflammasome functions are, and how that may be modulated by antagonistic effects of concomitant inflammasome activation as well as novel regulatory factors.

Figure 1

NLR domains and inflammasome components. NLRs are characterized by a common central nucleotide-binding/NACHT domain and a leucine-rich repeat domain. Different members of the NLR family are distinguished by domains residing in the variable N-terminal regions. They can include caspase-activation and recruitment (CARD), PYRIN (PYD), or BIR (baculovirus IAP repeat) domains. The ASC adaptor contains both CARD and PYD domains, while caspase-1 contains a CARD domain.

Figure 2

(Blue, left) TLR4 activation induces signaling pathways that upregulate transcription through NFκB. PKR is also phosphorylated upon activation of TLR4 signaling. Binding to NLRP1, NLRP3, NLRC4, and AIM2 enhances inflammasome function. (Gray, middle) The inhibitory association of thioredoxin (THX) to TXNIP is relieved in the presence of ROS. TXNIP is free to bind NLRP3 that enhances inflammasome function. GBP5 tetramerization is triggered by an as yet unknown stimulus that then promotes ASC oligomerization to amplify inflammasome activation. It is not clear if TXNIP remains bound to NLRP3 during this time. (Green, right) NLRC4 activation requires both flagellin and NAIP5/6 to induce an inflammasome response. PKCδ phosphorylation of NLRC4 may also enhance NLRC4 inflammasome activity. The kinetics of the NLRC4 phosphorylation and NAIP association during inflammasome function is not clear. Regardless of how inflammasomes are regulated, their engagement is required for pyroptosis and processing of pro-caspase-1, pro-IL-1β, and pro-IL-18.