The inflammasome is a multiprotein oligomer consisting of caspase 1,
PYCARD, NALP and sometimes caspase 5. It is expressed in myeloid cells and is a
component of the innate immune system. 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. The inflammasome promotes the maturation of the
inflammatory cytokines Interleukin 1β and Interleukin 18.
The inflammasome is responsible for activation of inflammatory processes,
and has been shown to induce cell pyroptosis, a process of programmed cell
death distinct from apoptosis. History
The inflammasome was discovered by the team of Prof. Jürg Tschopp, at the
University of Lausanne, in 2002. Function
During an infection, one of the first forms of defense employed by the innate
immune response is a group of pattern recognition receptors 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 and C-type
Lectin Receptors or inside the cytoplasm e.g. Nod-like receptors and RIG-I-like
receptors. 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 family, termed
absent in melanoma 2 which assembles upon sensing foreign cytoplasmic
double-stranded DNA. 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.
Inflammatory cascade Analogous to the apoptosome, which
activates apoptotic cascades, the inflammasome activates an inflammatory
cascade. Once active, the inflammasome binds to pro-caspase-1, either
homotypically via its own caspase activation and recruitment domain 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. NLR-subset inflammasomes
NLRP1, NLRP3 and NLRC4 are subsets of the NLR family and thus have two common
features: the first is a nucleotide-binding domain which is bound
to by ribonucleotide-phosphates and is important for self-oligomerization. The
second is a C-terminus leucine-rich repeat, which serves as a
ligand-recognition domain for other receptors or microbial ligands.
= NLRP1 = See NLRP1 for gene information
Structure In addition to NBD and LRR, NLRP1
contains at its N-terminal a pyrin domain 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.
Activation 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, 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. = NLRP3 =
See NALP3 for gene information Structure
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. Activation
NLRP3 oligomerization is activated by a large number of stimuli, which has
implicated studies into its activation pathway. Its activity has been shown to
be induced and/or increased by low intracellular potassium concentrations,
viruses e.g. influenza A and Neisseria gonorrhoeae, bacterial toxins e.g.
nigericin and maitotoxin, liposomes, urban particulate matter, and most
notably, crystallized endogenous molecules. Cholesterol crystals and
monosodium urate crystals increase NLRP3-induced IL-1β-production and this
process is thought to be abrogated in atherosclerosis and gout, where these
crystals form respectively in the cell. It has also been proven that inorganic
particles like Titaniumdioxide, Siliciumdioxide and asbestos trigger the
inflammasome-response. Pore-forming toxins and ATP-activated pannexin-1 may
also trigger K+ efflux and grant access of toxins into the cell to directly
activate NLRP3. = NLRC4 =
See NLRC4 for gene information Structure
NLRC4 is the only known subset of the NLRC family to form an inflammasome and
contains only a CARD domain in addition to the NBD and LRR, which it uses to
recruit procaspase-1 directly. Activation
NLRC4 is activated by bacteria, a number of which have been identified using
murine macrophage culture studies: Salmonella typhimurium, Legionella
pneumophila and Pseudomonas aeruginosa. The activation process by these bacteria
is unclear but is thought to require a type 3 or type 4 secretion system
provided by bacterial flagellin, which gains entry through the cell membrane
and is then detected by NLRC4, activating it.
AIM2 Main article: AIM2
AIM2 is an acronym for absent in melanoma 2, and is sometimes also
referred to as Interferon-inducible protein.
= Structure = AIM2 is a non-NLR family protein. It is
a 343 amino acid protein with pyrin and a HIN-200 domains, the former of which
is activated in AIM2 by dsDNA. = Function =
AIM2 is referred to as the DNA inflammasome for its ability to detect
foreign dsDNA, using a HIN200 domain attached to a PYD, which it uses to
recruit the adaptor protein ASC during inflammasome formation. AIM2 binds dsDNA
with its C-terminal domain. The PYDdomain of AIM2 homotypically
interacts by PYD-PYD interactions with ASC. The ASC CARD domain recruits
procaspase-1 into the complex. Caspase-1 activates maturation of proinflammatory
cytokines. AIM2 is activated by viral dsDNA, bacterial dsDNA and also aberrant
host dsDNA. Activation of the AIM2 is supposed to play role in autoimmune
responses during the autoimmune disease systematic lupus erythematosus.
Further reading Jin, Tengchuan & Xiao, Tsan Sam.
"Activation and assembly of the inflammasomes through conserved protein
domain families". Apoptosis 20: 151-156. doi:10.1007/s10495-014-1053-5. PMID
25398536. Retrieved 14 November 2015. Lu A & Wu H. "Structural mechanisms of
inflammasome assembly". FEBS J. 282: 435-444. doi:10.1111/febs.13133. PMID
25354325. Retrieved 14 November 2015. Shawa Neil & Liu Zhi-Jie. "Role of the
HIN Domain in Regulation of Innate Immune Responses". Mol. Cell Biol. 34:
2–15. doi:10.1128/MCB.00857-13. PMC 3911281. Retrieved 14 November 2015.
Walsh, JG, Muruve DA & Power C. "Inflammasomes in the CNS". Nature Rev.
Neurosci. 15: 84–97. doi:10.1038/nrn3638. Retrieved 14
November 2015. Schroder Kate & Tschopp Jurg. "The
Inflammasomes". Cell 140: 821–832. doi:10.1016/j.cell.2010.01.040.
Retrieved 14 November 2015. Jha S & Ting JP.
"Inflammasome-associated nucleotide-binding domain, leucine-rich
repeat proteins and inflammatory diseases". J Immunol 183: 7623–7629.
doi:10.4049/jimmunol.0902425. PMID 20007570. Retrieved 14 November 2015.
Stutz A, Golenbock DT, Latz E.. "Inflammasomes: too big to miss". J Clin
Invest 119: 3502–3511. doi:10.1172/JCI40599. PMC 2786809. PMID
19955661. Retrieved 14 November 2015. Fink SL, Cookson BT. "Apoptosis,
pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic
cells". Infect. Immun. 73: 1907–1916. doi:10.1128/IAI.73.4.1907-1916.2005. PMC
1087413. PMID 15784530. Retrieved 14 November 2015.
Martinon F & Tschopp Jurg. "NLRs join TLRs as innate sensors of pathogens".
Trends Immunol. 26: 447–54. doi:10.1016/j.cell.2010.01.040. PMID
15967716. Retrieved 14 November 2015. References