Inflammasomes and host defenses against bacterial infections

Abstract

The inflammasome has emerged as an important molecular protein complex which initiates proteolytic processing of pro-IL-1β and pro-IL-18 into mature inflammatory cytokines. In addition, inflammasomes initiate pyroptotic cell death that may be independent of those cytokines. Inflammasomes are central to elicit innate immune responses against many pathogens, and are key components in the induction of host defenses following bacterial infection. Here, we review recent discoveries related to NLRP1, NLRP3, NLRC4, NLRP6, NLRP7, NLRP12 and AIM2-mediated recognition of bacteria. Mechanisms for inflammasome activation and regulation are now suggested to involve kinases such as PKR and PKCδ, ligand binding proteins such as the NAIPs, and caspase-11 and caspase-8 in addition to caspase-1. Future research will determine how specific inflammasome components pair up in optimal responses to specific bacteria.

Figure 1. Model of NLRP3 activation

Activation of caspase-1 by the NLRP3 inflammasome is a multi-signal process. Signal 1 occurs when TNF or a TLR ligand binds its cognate receptor resulting in the translocation of NF-κB into the nucleus where expression of NLRP3 and the immature (pro-) forms of IL-1β and IL-18 are induced. Signal 2 is the activation of NLRP3 resulting in recruitment and cleavage of pro-caspase-1 to its active form leading to cleavage of the immature inflammatory cytokines. At least three distinct NLRP3 activation pathways have been identified. Phagocytosis of extracellular particulates and pathogens results in lysosomal destabilization and release of cathepsin B and bacterial mRNA which trigger NLRP3 activation. A decrease in intracellular K⁺ has been shown to result in activation of NLRP3. K⁺ efflux occurs by engagement of extracellular ATP with the P₂X₇R or directly through bacterial pore-forming toxins. ROS generated during mitochondrial damage and oxidized mitochondrial DNA (mtDNA) produced during apoptosis lead to activation of NLRP3. Td92, a surface protein of Treponema denticola, can interact with the α5β1 integrin resulting in ATP release and K⁺ efflux. Inhibition of ribosomal function and protein synthesis can also direct NLRP3 activation, and this mechanism may involve lysosomal destabilization, K⁺ efflux and ROS. Caspase-11 has been defined upstream of caspase-1 during NLRP3 inflammasome activation.

Figure 2. Inflammasome design and activators

Inflammasome-forming NLRs share the same general features, although mechanisms for ligand recognition may differ. NLRP3, 6, 7 and 12 all share a C-terminal leucine-rich-repeat (LRR) region, an internal nucleotide-binding-domain (NBD), and a N-terminal Pyrin domain (PYD), which recruits the adapter protein ASC - a caspase recruitment and activation domain (CARD) and PYD containing protein which links the NLR or AIM2 to caspase-1. The ASC adapter is believed to be an integral part of NLRP3, 6, 7 and 12 inflammasomes. NLRC4 contains an N-terminal CARD domain which can recruit caspase-1 directly, though ASC involvement may increase caspase-1 processing activity. NLRP1b, like NLRC4, has a N-terminal CARD domain, but has an internal LRR and a C-terminal NBD domain. Lastly, AIM2 has a HIN200 DNA binding domain and a PYD for ASC recruitment. Different types of stimuli signal inflammasome activation via the various NLRs or AIM2, some of which are depicted.