The inflammasome NLRs in immunity, inflammation, and associated diseases

Abstract

Inflammasome activation leads to caspase-1 activation, which causes the maturation and secretion of pro-IL-1β and pro-IL-18 among other substrates. A subgroup of the NLR (nucleotide-binding domain, leucine-rich repeat containing) proteins are key mediators of the inflammasome. Studies of gene-deficient mice and cells have implicated NLR inflammasomes in a host of responses to a wide range of microbial pathogens, inflammatory diseases, cancer, and metabolic and autoimmune disorders. Determining exactly how the inflammasome is activated in these diseases and disease models remains a challenge. This review presents and integrates recent progress in the field.

Figure 1

Activators of the inflammasome. Activators of the inflammasome are divided into two categories: Sterile activators include host- and environment-derived molecules, and pathogen-associated activators include PAMPs derived from bacteria, virus, fungus, and protozoa. Assembly of the NLRs, ASC, and caspase-1 leads to the formation of a penta- or heptamer structure: the inflammasome. Activation of the inflammasome leads to maturation and secretion of IL-1β and IL-18 as well as inflammatory cell death, by either pyroptosis or pyronecrosis.

Figure 2

Models of inflammasome activation. Coordination of a manifold series of signals culminates in the activation of the inflammasome. Three models have been put forth to explain mechanisms of inflammasome activation. The observation that inflammasomes are activated by a diverse array of biological molecules suggests an indirect mechanism of sensing as opposed to a direct interaction with a receptor ligand pair. Reactive oxygen species (ROS) are induced by many of the known activators of inflammasomes. It is postulated that the generation of ROS, possibly via the phagosomal NADH-oxidase, releases thioredoxin-interacting protein (TXNIP) from thioredoxin (TRX). TXNIP, which is free from TRX, can bind to NLRP3, possibly by competing with HSP90 and SGT1, which retain NLRP3 in an inactive state. The NLRP3 TXNIP complex facilitates inflammasome formation through an unknown mechanism that might relate to the activity of superoxide dismutase (SOD1). Alternatively, the release of cathepsin B (and possibly other cathepsins) due to lysosomal destabilization activates the inflammasome during phagocytosis. How cathepsin B activates the inflammasome is currently unknown, but activation requires its enzymatic activity. The final model posits pore formation at the plasma membrane that allows for K⁺ efflux. Pore formation can occur via the P2X7 receptor/pannexin-1 oligo-structure via pathogen toxins or ion channels. A modification to the last model suggests that small PAMPs can gain cytosolic access via the P2X7 receptor/pannexin-1 hemichannel and activate the inflammasome.

Figure 3

Inhibitors of the inflammasome. Inhibitors of the inflammasome are divided into two categories: endogenous and exogenous. The inhibitors of the inflammasome are dynamic in nature. The molecular mechanisms that facilitate inhibition are poorly understood. Nonetheless, their existence underscores the importance of this pathway in controlling inflammation.

Figure 4

In vivo activation of inflammasomes. During infection, injury, or sterile inflammation, the inflammasome becomes directly and indirectly activated. The initial event leads to caspase-1 activation, IL-1β and IL-18 secretion, and cell death. Cell death can release a second series of inflammasome agonists such as ATP, hyaluronan, and uric acid that can activate the inflammasome in a paracrine manner to augment the response. The elaboration of IL-1β and IL-18 contributes to the recruitment of additional effector cell populations. The perpetuation of the inflammatory cascade culminates either in resolution of inflammation and infection or in chronic inflammatory diseases.