NLR‐containing inflammasomes: Central mediators of host defense and inflammation

Since its discovery of 25 years ago, the basic mechanisms through which IL-1 drives inflammation and contributes to the pathogenesis of inflammatory diseases have been well documented (reviewed in [1]). The underlying mechanisms responsible for IL-1 production, however, have only been uncovered relatively recently. A major breakthrough in this regard was the purification in 2002 by Tschopp and colleagues of the inflammasome [2], a large multiprotein complex that assembles in cells and leads to the activation of the proteolytic enzyme caspase-1. To date, four inflammasome complexes have been partially characterized, containing NLRP1 [3], NLRP3 [4], IPAF/NLRC4 [5] or AIM2 [6–9] (Fig. 1). The NLR proteins (officially called the nucleotide-binding domain and leucine-rich repeat (LRR)-containing receptors, although almost exclusively called the NOD (nucleotide-binding oligomerization domain)-like receptors by the research community) are a family of intracellular immune receptors with more than 20 members currently known in humans. The largest group of these are characterized by the presence of an amino terminal pyrin domain (PYD), caspase activation and recruitment domain (CARD) or baculovirus inhibitory repeat domain followed by a nucleotide-binding domain, and LRRs at the Cterminus. Upon activation, the NLR are thought to oligomerize via homotypic interactions between NACHT domains thereby clustering PYD domains, which recruit an adapter molecule called apoptosis-associated speck-like protein containing a CARD (ASC). ASC assembly facilitates the recruitment of procaspase-1. Procaspase-1 clustering, in turn, leads to autocleavage and generation of active caspase-1, which cleaves and activates the pro-inflammatory cytokines IL-1b and IL-18. In this Viewpoint series, leading experts studying NLR have been commissioned by the editorial team at the European Journal of Immunology to describe recent developments related to these important host sensors. A special Viewpoint from Charles Dinarello recounts the critical discoveries in the field of IL-1 biology and NLR inflammasomes, celebrating the 25th anniversary of the cloning of IL-1 [10]. The following 11 Viewpoint articles detail the discovery and characterization of inflammasome complexes, describing their role in host defense and sterile inflammation and address the role of the NLR in adjuvanticity, auto-inflammatory diseases, as well as the pathogenesis of other inflammasome-mediated diseases. These Viewpoints highlight the impact of the NLR on our understanding of the basic mechanisms of host defense and reveal how the progress made over the past decade has reshaped our understanding of inflammatory disease pathogenesis. The pro-inflammatory cytokine IL-1b is among the arsenal of defense measures deployed by the innate immune system to combat invading microbes. Its proinflammatory activity is regulated at the level of expression, processing and secretion [11], although additional control occurs via antagonism by IL-1 receptor antagonist (IL-1RA). Several classes of innate immune receptors including the TLR and the C-type lectin Dectin-1, induce pro-IL-1 expression [12, 13]; however, caspase-1 activation is only mediated by the NLR or AIM2 inflammasomes. In the Viewpoint by Nunez and colleagues, the role of the NLR in regulating caspase-1 activity and IL-1b production during microbial infection is described [14]. NLRP1 has been shown to form an inflammasome in response to muramyl dipeptide, as well as to anthrax lethal toxin in mice. NLRP3 inflammasomes form in cells infected with bacteria (Staphlococcus aureus, Listeria monocytogenes, Escherichia coli, Mycobacterium marinarum and Neisseria gonnorrhoeae), viruses (Sendai, influenza and adenovirus) and fungi (Candida albicans), as well as in response to products from these and other pathogens. IPAF senses flagellin and was considered a devoted flagellin sensor; however, a recent study suggests that IPAF can mediate caspase-1 activation independent of flagellin [15]. The role of the NLR inflammasomes is not confined to sensing microbial infection; Cassel and Sutterwala describe how NLRP3 responds to endogenous molecules