Inflammasome

The inflammasome is a multiprotein oligomer responsible for the activation of inflammatory responses. The inflammasome promotes the maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). The secretion of these cytokines results in pyroptosis, a form of programmed pro-inflammatory cell death distinct from apoptosis. In the case of dysregulation of the inflammasome, an assortment of major diseases may arise. It is expressed in myeloid cells and is a component of the innate immune system. The inflammasome complex can consist of caspase 1, PYCARD, NALP and sometimes caspase 5 (also known as caspase 11 or ICH-3). NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) and ALRs (AIM2-like receptors) can also form an inflammasome. The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly, e.g. dsRNA will trigger one inflammasome composition whereas asbestos will assemble a different variant. Because the pro-inflammatory pathway does not need Toll-like receptors (TLRs), inflammasomes with AIM2 can detect cytoplasmic DNA, a danger signal, that may be threatening and strengthen their innate response. The inflammasome is a multiprotein oligomer responsible for the activation of inflammatory responses. The inflammasome promotes the maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). The secretion of these cytokines results in pyroptosis, a form of programmed pro-inflammatory cell death distinct from apoptosis. In the case of dysregulation of the inflammasome, an assortment of major diseases may arise. It is expressed in myeloid cells and is a component of the innate immune system. The inflammasome complex can consist of caspase 1, PYCARD, NALP and sometimes caspase 5 (also known as caspase 11 or ICH-3). NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) and ALRs (AIM2-like receptors) can also form an inflammasome. The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly, e.g. dsRNA will trigger one inflammasome composition whereas asbestos will assemble a different variant. Because the pro-inflammatory pathway does not need Toll-like receptors (TLRs), inflammasomes with AIM2 can detect cytoplasmic DNA, a danger signal, that may be threatening and strengthen their innate response. The inflammasome was discovered by the team of Dr. Jürg Tschopp, at the University of Lausanne, in 2002. Tschopp and team were able to articulate the inflammasome's role in diseases such as gout and type 2 diabetes. They found that a variety of danger signals could provoke a response from an inflammasome including viral DNA, muramyl dipeptide (MDP), asbestos, and silica. Tschopp and his colleagues found a connection between metabolic syndrome and NLRP3, a subset type of inflammasome. Within their research on NLRP3, they were able to show that when NLRP3 is inhibited, an immunosuppressive behavior of type I interferon was exhibited. Ultimately, the work of Dr. Tschopp and his team led to the research and eventual treatments of many major diseases and ailments. During an infection, one of the first forms of defense employed by the innate immune response is a group of pattern recognition receptors (PRRs) encoded in the germline to recognize molecular patterns expressed by invading pathogens. These may either be on the membrane surface e.g. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) or inside the cytoplasm e.g. Nod-like receptors (NLRs) and RIG-I-like receptors (RLRs). In 2002, it was first reported by Martinon et al. that a subset of NLRs named NLRP1 were able to assemble and oligomerize into a common structure which collectively activated the caspase-1 cascade, thereby leading to the production of pro-inflammatory cytokines especially IL-1B and IL-18. This NLRP1 multi-molecular complex was dubbed the ‘inflammasome’, which spurred much interest in the following years; since then, several other inflammasomes were discovered, two of which are also NLR subsets—NLRP3 and NLRC4. More recently, Hornung et al. classified an inflammasome of the PYHIN (pyrin and HIN domain-containing protein) family, termed absent in melanoma 2 (AIM2) which assembles upon sensing foreign cytoplasmic double-stranded DNA (dsDNA). Notably, the pyrin domain of the adaptor protein ASC has recently been shown to function as a prion-like domain, through a self-perpetuating manner upon activation. Analogous to the apoptosome, which activates apoptotic cascades, the inflammasome activates a pyroptotic inflammatory cascade. Once active, the inflammasome binds to pro-caspase-1 (the precursor molecule of caspase-1), either homotypically via its own caspase activation and recruitment domain (CARD) or via the CARD of the adaptor protein ASC which it binds to during inflammasome formation. In its full form, the inflammasome appositions together many p45 pro-caspase-1 molecules, inducing their autocatalytic cleavage into p20 and p10 subunits. Caspase-1 then assembles into its active form consisting of two heterodimers with a p20 and p10 subunit each. Once active, it can then carry out a variety of processes in response to the initial inflammatory signal. These include the proteolytic cleavage of pro-IL-1B at Asp116 into IL1β, cleavage of pro-IL-18 into IL-18 to induce IFN-γ secretion and natural killer cell activation, cleavage and inactivation of IL-33, DNA fragmentation and cell pore formation, inhibition of glycolytic enzymes, activation of lipid biosynthesis and secretion of tissue-repair mediators such as pro-IL-1α. Additionally, AIM2 contains a HIN200 domain which senses and binds foreign cytoplasmic dsDNA and activates NF-κB, a role that is crucial in bacterial and viral infection. NLRP1, NLRP3 and NLRC4 are subsets of the NLR family and thus have two common features: the first is a nucleotide-binding domain (NBD) which is bound by ribonucleotide-phosphates (rNTP) and is important for self-oligomerization. The second is a C-terminus leucine-rich repeat (LRR), which serves as a ligand-recognition domain for other receptors (e.g. TLR) or microbial ligands. NLRP1 has been found in neurons, while both NLRP3 and NLRC4 (IPAF) have been identified in microglial cells. In addition to NBD and LRR, NLRP1 contains at its N-terminal a pyrin domain (PYD) and at its C-terminal an FIIND motif and a CARD which distinguishes it from the other inflammasomes. Upon activation, the C-terminal CARD homotypically interacts with the CARD of procaspase-1 or procaspase-5, while its N-terminal PYD homotypically interacts with the PYD of adaptor protein ASC, whose CARD can then recruit another pro-caspase-1. The overall recruitment and cleavage of procaspase-1 can then activate all downstream caspase-1 pathways. The mechanism of NLRP1 activation is unclear but has been proposed by Reed and colleagues to be a two-step process involving first activation by microbial ligands, followed by binding of an rNTP to the nucleotide-binding domain of NLRP1. NLRP1 has been shown to confer macrophage sensitivity to anthrax lethal toxin (LT), suggesting the role of bacterial toxins in inducing inflammasome formation. NLRP1 activity is regulated by anti-apoptotic proteins Bcl-2 and Bcl-x(L) which, in resting cells, associate with and inhibit NLRP1 activity. In addition to the NBD and LRR domains, NLRP3 contains a PYD domain like NLRP1 and thus activates caspase-1 the same way, using its PYD to recruit ASC. It forms only one oligomer per cell, and its oligomer is made of seven NLRP3 molecules. It is known to be the biggest inflammasome of all, covering about 2 um in diameter.