The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis

Abstract

The inflammasome is a multiprotein complex that mediates the activation of caspase-1, which promotes secretion of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18, as well as 'pyroptosis', a form of cell death induced by bacterial pathogens. Members of the Nod-like receptor family, including NLRP1, NLRP3 and NLRC4, and the adaptor ASC are critical components of the inflammasome that link microbial and endogenous 'danger' signals to caspase-1 activation. Several diseases are associated with dysregulated activation of caspase-1 and secretion of IL-1beta. Thus, understanding inflammasome pathways may provide insight into disease pathogenesis that might identify potential targets for therapeutic intervention.

Figure 1

The NLRC4 inflammasome. Infection of macrophages with several Gram-negative bacteria including Salmonella, Legionella and Pseudomonas activates caspase-1 through NLRC4 and ASC. A critical step is the cytosolic delivery of flagellin via bacterial T3SS or T4SS. Shigella activates the NLRC4 inflammasome independent of flagellin through an unknown microbial molecule. Activation of caspase-1 via NLRC4 leads to processing and secretion of IL-1β and IL-18 as well as other activities.

Figure 2

The NLRP3 inflammasome. Activation of caspase-1 through NLRP3 is induced by co-stimulation with microbial molecules such as LPS and the P2X7R, pore-forming molecules or particulate matter (e. g. silica, asbestos, urate crystals, and fibrilar β-amyloid). Stimulation of the P2X7R by extracellular ATP induces the activation of a cation channel that mediates K⁺ efflux, an event that has been linked to inflammasome activation. In addition, P2X7R activation promotes the opening of the pannexin-1 pore which may mediate cytosolic delivery of microbial molecules such as MDP. The mechanism of NLRP3 activation in the cytosol remains poor understood. There is evidence that it may involve, at least in part, lysosomal membrane destabilization and cathepsin B activation (in the case of silica, urate crystals and fibrilar β-amyloid). TLR stimulation also induces the activation of the NLRP3 inflammasome through TRIF when the autophagy machinery is compromised (e.g. Atg16L or Atg7 deficiency). ROS have been also implicated in the activation of the NLRP3 inflammasome.