Sensing and reacting to microbes through the inflammasomes

Abstract

Inflammasomes are multiprotein complexes that activate caspase-1, which leads to maturation of the proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 and the induction of pyroptosis. Members of the Nod-like receptor (NLR) family, including NLRP1, NLRP3 and NLRC4, and the cytosolic receptor AIM2 are critical components of inflammasomes and link microbial and endogenous danger signals to the activation of caspase-1. In response to microbial infection, activation of the inflammasomes contributes to host protection by inducing immune responses that limit microbial invasion, but deregulated activation of inflammasomes is associated with autoinflammatory syndromes and other pathologies. Thus, understanding inflammasome pathways may provide insight into the mechanisms of host defense against microbes and the development of inflammatory disorders.

Figure 1

The Nlrc4 inflammasome. Infection of macrophages with several Gram-negative bacteria including Salmonella, Legionella and Pseudomonas activates Caspase-1 through Nlrc4. A critical step is the cytosolic delivery of flagellin or PrgJ-like proteins via bacterial T3SS or T4SS. Flagellin is recognized by Naip5 or Naip6 (not depicted) whereas PrgJ-like proteins are recognized by Naip2. Shigella activates the Nlrc4 inflammasome independently of flagellin through an unknown microbial product. Activation of Caspase-1 via Nlrc4 leads to processing and secretion of IL-1β and IL-18 as well as other cellular activities that are poorly understood.

Figure 2

The Nlrp3 inflammasome. Activation of Caspase-1 through Nlrp3 requires two signals. Signal 1 is represented by microbial molecules or endogenous cytokines and is required for the upregulation of Nlrp3 and pro-IL-1β. Signal 2 activates the Nlrp3 inflammasome. Activation by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae and Vibrio cholere is mediated by pore-forming toxins. In addition, other bacterial toxins can induce the activation of the Nlrp3 inflammasome, such as Cholera Toxin (CT) or Clostridium difficile toxins TcdA and TcdB (not depicted); Candida albicans induces the activation of the Nlrp3 inflammasome through the kinase Syk, although the mechanism involved is unclear. Influenza virus can induce the activation of the Nlrp3 inflammasome, but whether this is due to a pore-forming activity mediated by M protein or to sensing of viral RNA species in the cytosol remains controversial. Cytosolic bacterial RNA has been reported to induce the activation of the Nlrp3 inflammasome.