The inflammasomes: mechanisms of activation and function

Abstract

In response to injurious or infectious agents caspase-1 activating multiprotein complexes, termed inflammasomes, assemble in the cytoplasm of cells. Activated caspase-1 cleaves the proforms of the interleukin-1 cytokine family members leading to their activation and secretion. The IL-1 family cytokines have multiple proinflammatory activities implicating them in the pathogenesis of many inflammatory diseases. While defined ligands have been identified for the NLRP1, IPAF, and AIM2 inflammasomes, little is known about the activation mechanisms of the NLRP3 inflammasome. Numerous different molecular entities, such as various crystals, pore-forming toxins, or extracellular ATP can trigger the NLRP3 inflammasome. Recent work proposes that NLRP3 is activated indirectly by host factors that are generated in response to NLRP3 triggers.

Figure 1. Schematic of characterized inflammasomes

The NLRP1 inflammasome consists of a NACHT and LRR domains and can bind to caspase-5 via the C-terminal CARD domain and to the adapter molecule ASC via the N-terminal PYD domain. ASC interacts with caspase-1 via its CARD domain. Muramyl dipeptide (MDP) and lethal factor of Bacillus anthracis are presumed to interact with the LRRs of NLRP1. NLRP3 has LRRs possibly interacting with an intermediate molecule that is generated by cathepsin and/or ROS activity. The NACHT domain can associate with ATP and NLRP3 binds to ASC via its N-terminal PYD domain. ASC, in turn, associates with caspase-1. The NLRC4 inflammasome consists of LRR domains that could interact with bacterial flagellin and a NACHT domain followed by an N-terminal CARD domain. The CARD domain can either directly interact with caspase-1 or via the CARD domain of ASC. The AIM2 inflammasome can directly interact with double-stranded DNA through its C-terminal HIN200 domain. AIM2 activates caspase-1 via ASC at the N-terminus of the protein.

Figure 2. Possible scenarios leading to NLRP3 inflammasome activation

A. A protease acts on a cytoplasmic protein and the cleavage product binds to and activates NLRP3. B. NLRP3 is auto-inhibited by binding to a protease sensitive protein. After cleavage of the NLRP3 interacting protein, NLRP3 becomes deinhibited and activated. C. Reactive oxygen species act on a substrate in the cytoplasm of cells, which becomes modified and acts as an activator of the NLRP3 inflammasome. D. A combination of an ROS-mediated activator and protease cleaved inhibitor could act to activate the NLRP3 inflammasome.