Inflammasomes

Inflammasomes are a group of multimeric protein oligomers that activate pro-inflammatory cytokines in response to infection and tissue damage. Inflammasomes are part of the innate immune system, triggering an inflammatory response by activating caspases.

A canonical inflammasome consists of a sensor molecule, which binds to caspase 1 via the adaptor protein ASC (apoptosis-associated speck-like protein). The exact composition of the inflammasome is determined by the type of activator. The most common sensor molecules are NOD-like receptors (NLRs); these include the subtypes NLRP1 (NOD-, LRR- and pyrin domain-containing 1), NLRP3, NLRP6, NLRP7, NLRP12, AND NLRC4 (NOD-, LRR- and CARD-containing 4; IPAF). Other sensor molecules include PYHIN, AIM2 and IFI16, in addition, RIG-1 has been postulated to play a role in stimulating the assembly of inflammasomes. Inflammasome sensor molecules are able to detect a broad range of microorganisms and tissue stress, for example NLRP12 can detect bacterial peptidoglycan; NLRC4 can detect microbial proteinaceous ligands; PYHIN and RIG-1 detect nucleic acids; while NLRP3 can detect bacterial toxins and peptide aggregates.

When sensor molecules are stimulated by bacterial or viral molecules that contain pathogen-associated molecular patterns (PAMPs), or by non-microbial danger signals (DAMPs) produced by damaged cells, they bind to ASC proteins via the pyrin domain. The ASC proteins assemble into multimers of ASC dimers, which then bind pro-caspase 1 via the caspase activation and recruitment domain (CARD); this initiates caspase self-cleavage into the active p20 and p10 subunits. These active heterotetrameric caspase-1 complexes promote the activation of inflammatory cytokines, including IL-1β and IL-18 (secretion via a non-classical pathway), which in turn recruit and activate immune cells such as neutrophils. Inflammasomes can also induce pyroptosis, a highly inflammatory form of programmed cell death, promoting rapid clearance of bacterial and viral infections.

Canonical Inflammasome Assembly

Figure 1: A canonical inflammasome consists of a sensor molecule, an adaptor protein and a pro-caspase. These form a multimeric protein oligomer that activate pro-inflammatory cytokines, as part of the innate immune system. The sensor molecule is made up of a leucine-rich repeat (LLR) domain, which has regulatory functions and is involved in ligand recognition; a central nucleotide-binding domain (NBD) domain, which has ATPase activity and is involved in oligomerization of the inflammasome; and a pyrin death fold domain, which binds the ASC protein. Activated sensor molecules bind the adaptor protein ASC, which in turn binds to pro-caspase via the CARD domain. This initiate the self-cleavage of pro-caspase in to active subunits p10 and p20, which then active pro-inflammatory cytokines.

In addition to canonical three component inflammasomes, several non-canonical inflammasomes have been described. These include a NLRP3 inflammasome, which is made up of its sensor module NLRP3, ASC, caspase-1 and caspase-11. This inflammasome is thought to be important in monitoring cellular and mitochondrial stress. NLRP3 is able to detect oxidized mitochondrial DNA, which has been released into the cytosol, as well as high levels of reactive oxygen species (ROS). NLRP3 inflammasome activation is also regulated by intracellular levels of K⁺, Cl^- and Ca²⁺.

Disease Implications

Regulation of inflammasome assembly is a tightly controlled process that ensures the removal of pathogens and the restoration of damaged tissue, without damaging the host. As part of the innate immune system, inflammasome activation provides a first response to pathogen attack and tissue trauma. Once the adaptive immune system has been triggered this primitive response is no longer required and memory CD4⁺ T cells inhibit NLRP1 and NLRP3 inflammasome activation. Dysregulation of inflammasome activity has been linked to type 2 diabetes, cancer, atherosclerosis and neurodegenerative diseases.

Inflammasomes are also being studied by HIV researchers. The onset of AIDS is associated with chronic inflammation and the progressive loss of CD4⁺ T cells. HIV-1 infection triggers proinflammatory cytokine secretion and pyroptosis in these cells, selectively destroying them. This creates a pathogenic cycle in which dying infected CD4⁺ T cells release more inflammatory cytokines and attract more CD4⁺ T cells to the same fate. Inflammatory cytokine processing and release are regulated by caspase-1 activation in inflammasomes. Researchers are targeting inflammasomes to break this cycle by inhibiting caspase-1 activation.