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Inflammasomes are
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
multiprotein
oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relati ...
s of the
innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of Gasdermin-D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
, referred to as
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
, and is responsible for secretion of the mature
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s, presumably through the formation of pores in the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. Inflammasome activation is initiated by different kinds of cytosolic
pattern recognition receptor Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
s (PRRs) that respond to either microbe-derived
pathogen-associated molecular pattern Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
s (PAMPs) or
danger-associated molecular patterns Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated ...
(DAMPs) generated by the host cell.
Pattern recognition receptor Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
s involved in inflammasomes comprise NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) as well as AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16 ) as well as pyrin. Through their caspase activation and recruitment domain (CARD) or pyrin domain (PYD), the inflammasome receptors interact with the adaptor protein ASC, which then recruits pro-
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
via its CARD domain and activates the effector
caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyste ...
through proteolytic cleavage. The activated
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
finally cleaves the immature pro-inflammatory
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s pro-
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
and pro- IL-18, as well as Gasdermin-D, which are responsible for inflammatory signaling and pyroptotic cell death, respectively. In addition to these so-called canonical inflammasomes, different studies also described non-canonical inflammasome complexes that act independently of
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
. In mice, the non-canonical inflammasome is activated by direct sensing of cytosolic bacterial
lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O- antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the out ...
(LPS) by caspase-11, which subsequently induces pyroptotic cell death. In human cells, the corresponding
caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyste ...
s of the non-canonical inflammasome are
caspase 4 Caspase 4 is an enzyme that proteolytically cleaves other proteins at an aspartic acid residue (LEVD-), and belongs to a family of cysteine proteases called caspases. The function of caspase 4 is not fully known, but it is believed to be an inf ...
and caspase 5. Traditionally, inflammasomes have mainly been studied in professional
immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...
of the
innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
, such as
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s. More recent studies, however, indicate high levels of inflammasome component expression in
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
barrier tissues, where they have been shown to represent an important first line of defense. In the case of dysregulation of inflammasome activation, an assortment of major diseases, such as cancer, autoimmune, metabolic and neurodegenerative diseases may arise.


Discovery

The inflammasome was discovered by the team of
Jürg Tschopp Jürg Tschopp (born 1951 in Basel — died 22 March 2011 in the Swiss Alps) was a Swiss biochemist, known for his research on apoptosis and the immunology of inflammation. His greatest achievement was perhaps his team's discovery and scientific des ...
, at the
University of Lausanne The University of Lausanne (UNIL; french: links=no, Université de Lausanne) in Lausanne, Switzerland was founded in 1537 as a school of Protestant theology, before being made a university in 1890. The university is the second oldest in Switzer ...
, in 2002. Tschopp and team were able to articulate the inflammasome's role in diseases such as
gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...
and
type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
. They found that a variety of danger signals could provoke a response from an inflammasome including viral DNA,
muramyl dipeptide Muramyl dipeptide is constituent of both Gram-positive and Gram-negative bacteria composed of N-acetylmuramic acid linked by its lactic acid moiety to the N-terminus of an L-alanine D-isoglutamine dipeptide. It can be recognized by the immune sy ...
(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 The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
was exhibited. Ultimately, the work of Tschopp and his team led to the research and eventual treatments of many major diseases and ailments. 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. In 2009, Hornung ''et al.'' classified an inflammasome of the PYHIN (
pyrin ''MEFV'' (Mediterranean fever) is a human gene that provides instructions for making a protein called pyrin (also known as marenostrin). Pyrin is produced in certain white blood cells (neutrophils, eosinophils and monocytes) that play a role in i ...
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.


Inflammation activation

The inflammasome activates a pyroptotic inflammatory cascade. Once active, the inflammasome binds to pro-caspase-1 (the precursor molecule of
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
), either homotypically via its own caspase activation and recruitment domain (CARD) or via the CARD of the adaptor protein
ASC ASC may refer to: Educational institutions * Anglican Schools Commission, Australia * Andres Soriano Colleges of Bislig, located in Surigao del Sur, Philippines * Agnes Scott College, Decatur, Georgia Organizations Australia * Australian Singi ...
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 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
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-1β at Asp116 into
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
, cleavage of pro-IL-18 into IL-18, as well as cleavage of Gasdermin-D to release its N-terminal fragment responsible for the induction of
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
, an immunostimulatory form of programmed cell death in which the cell releases its cytoplasmic content to induce pro-inflammatory signaling.
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
and IL-18 released following inflammasome activation were found to induce IFN-γ secretion and
natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repre ...
activation, cleavage and inactivation of IL-33, DNA fragmentation and cell pore formation, inhibition of glycolytic
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
, 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, a role that is crucial in bacterial and viral
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
.


Inflammasome family

NLRP1, NLRP3, NLRP6 and
NLRC4 NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the ''NLRC4'' gene. Structure The NLRC4 protein is highly conserved across mammalian species. It bears homology to the ''C. elegans'' Ced4 protein. It cont ...
are subsets of the NLR family and thus have two common features: the first is a nucleotide-binding oligomerization domain (NOD) which is bound by ribonucleotide-phosphates (rNTP) and is important for self-oligomerization. The second is a C-terminal
leucine-rich repeat A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These tandem repeats com ...
(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. Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC or Pycard) plays a key role in activation of the inflammasome. ASC helps recruit caspase-1 to associate with NLRs in the inflammasome complex via its CARD domain. ASC also has duties independent of the inflammasome as it has been shown to be required for
MHC class II MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cell ...
to present antigenic peptides in
dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. Th ...
s.


NLRP1 inflammasome

In addition to NOD and LRR, NLRP1 contains at its N-terminal a
pyrin domain A pyrin domain (PYD, also known as PAAD/DAPIN) is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the py ...
(PYD) and at its
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein i ...
an FIIND motif and a CARD, which distinguishes it from the other inflammasomes. While there is only one NLRP1 protein present in humans, rodents were found to have different
paralogues Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
. 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 ASC may refer to: Educational institutions * Anglican Schools Commission, Australia * Andres Soriano Colleges of Bislig, located in Surigao del Sur, Philippines * Agnes Scott College, Decatur, Georgia Organizations Australia * Australian Singi ...
, 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. NLRP1B in mice and NLRP2 in rats were found to be responsive to ''
Bacillus anthracis ''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent ( obligate) pathogen within the genus '' Bacillus''. Its infection is a ...
'' lethal toxin. The ''B. anthracis'' lethal factor proteolytically cleaves NLRP1B, which leads to
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
of the receptor and targeting for degradation by the
proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...
. This degradation generates a clipped C-terminal fragment, that subsequently binds to the rest of the protein in a non-covalent manner. During this process, a CARD on the C-terminal fragment becomes accessible for inflammasome assembly. So far, this activation mechanism depending on degradation by the proteasome machinery is unique among inflammasomes. NLRP1 activity is regulated by anti-apoptotic proteins
Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...
and Bcl-x(L) which, in resting cells, associate with and inhibit NLRP1 activity.


NLRP3 inflammasome

In addition to the NOD 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. NLRP3 oligomerization is activated by a large number of stimuli, including both PAMPs and DAMPs, which has implicated studies into its activation pathway. Examples of such stimuli from the DAMP group are crystalline matter such as monosodium urate (MSU) crystals,
alum An alum () is a type of chemical compound, usually a hydrated double sulfate salt of aluminium with the general formula , where is a monovalent cation such as potassium or ammonium. By itself, "alum" often refers to potassium alum, with the ...
or
asbestos Asbestos () is a naturally occurring fibrous silicate mineral. There are six types, all of which are composed of long and thin fibrous crystals, each fibre being composed of many microscopic "fibrils" that can be released into the atmosphere b ...
, calcium influx,
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
reactive oxygen species (ROS), and extracellular ATP. The NLRP3 inflammasome was also found to respond to
PAMPs Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
of different pathogens, such as viruses, e.g. influenza A, bacteria, e.g.
Neisseria gonorrhoeae ''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular), or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gon ...
, and bacterial toxins e.g.
nigericin Nigericin is an antibiotic derived from ''Streptomyces hygroscopicus''. Its isolation was described in the 1950s, and in 1968 the structure could be elucidated by X-ray crystallography. The structure and properties of nigericin are similar to the ...
and
maitotoxin Maitotoxin (or MTX) is an extremely powerful biotoxin produced by ''Gambierdiscus toxicus'', a dinoflagellate species. Maitotoxin has been shown to be more than one hundred thousand times more potent than VX nerve agent. Maitotoxin is so potent t ...
. All NLRP3 activators induce cytosolic
potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...
efflux from cells and a sufficiently low cytosolic potassium concentration is capable of triggering NLRP3 activation in the absence other activators. Hence, the downstream point where all the different NLRP3 stimuli converge appears to be low intracellular potassium concentrations. NLRP3 inflammasome activation by
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
crystals and MSU crystals increase NLRP3-induced IL-1β-production and this process is thought to be abrogated in atherosclerosis and
gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...
, where these crystals form in the cell. It has also been proven that inorganic particles like titanium dioxide, silicon dioxide and asbestos can trigger activation of the inflammasome. One study even indicates that NLRP3 inflammasome activation is involved in sleep regulation. Recent studies show that NLRP3 inflammasome-mediated neuroinflammation is involved in secondary brain injury after intracerebral hemorrhage. The major endogenous product of
lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chai ...
, 4-hydroxynonenal, directly bound to NLRP3 and inhibited the NLRP3 inflammasome activation independently of Nrf2 and
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
signaling


NAIP/NLRC4 inflammasome

NLRC4 is the subset of the NLRC family to form an inflammasome and contains only a CARD domain in addition to the NOD and LRR, which it uses to recruit the adaptor protein ASC or pro-caspase-1 directly. The NAIP/NLRC4 inflammasome is involved in host defense. In mouse, NAIPs are activated by binding to the bacterial
PAMPs Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
in the cytosol, given by the rod (NAIP2) and needle (NAIP1) components of the bacterial type-3 secretion system (T3SS), as well as
flagellin Flagellin is a globular protein that arranges itself in a hollow cylinder to form the filament in a bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons. Flagellin is the principal component of bacterial flagella, and is pres ...
, the molecular building block of
flagella A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide motility. Many protists with flagella are termed as flagellates. A microorganism may have fro ...
(NAIP5 and 6). In humans, there is only one NAIP, and it responds only to needle component. Following ligand binding, NAIPs interact with NLRC4 to initiate the assembly of the NAIP/NLRC4 inflammasome, which then recruits and activates pro-caspase-1 via its CARD domain. Palmitate has been shown experimentally to induce the NLRC4 inflammasome without any bacteria present. The NAIP/NLRC4 inflammasome is the best described epithelial inflammasome and plays an important role in the restriction of intraepithelial bacterial populations during early stages of enterobacterial infection with e.g. ''
Salmonella ''Salmonella'' is a genus of rod-shaped (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two species of ''Salmonella'' are '' Salmonella enterica'' and '' Salmonella bongori''. ''S. enterica'' is the type species and is ...
'' and '' Citrobacter rodentium''. Intracellular bacteria trigger activation of the inflammasome, which results in specific expulsion of infected epithelial cells from the epithelium in order to reduce the bacterial loads. This process is also referred to as epithelial
cell extrusion Cell extrusion, discovered in 2001, is a process conserved in epithelial from humans to sea sponge to seamlessly remove unwanted or dying cells while maintaining the integrity of the epithelial barrier. If cells were to die without extrusion, gap ...
, and occurs without compromising the integrity of the epithelial barrier. Furthermore, the NAIP/NLRC4 inflammasome was found to reduce tumor loads in a mouse model of
colorectal carcinoma Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
(CRC), by triggering the removal of tumor-initiating cells.


AIM2 inflammasome

'' Main article: AIM2'' The AIM2 inflammasome is a detector of cytosolic double stranded DNA (dsDNA) and plays an important role in the coordination of immune defense to DNA virus infections, as well as intracellular bacterial infections. AIM2 is activated by viral dsDNA,
bacterial Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were amon ...
dsDNA and also aberrant host dsDNA., and consequently it has been linked to different human diseases. For example autoinflammation in
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...
disease was found to be connected to recognition of self-DNA by AIM2. Furthermore, activation of the AIM2 is supposed to play role in autoimmune responses during the
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
disease systematic lupus erythematosus. The AIM2 inflammasome is also activated by pharmacological disruption of nuclear envelope integrity. AIM2 binds dsDNA with its C-terminal HIN-200 domain. The PYDdomain of AIM2 homotypically interacts by PYD-PYD interactions with
ASC ASC may refer to: Educational institutions * Anglican Schools Commission, Australia * Andres Soriano Colleges of Bislig, located in Surigao del Sur, Philippines * Agnes Scott College, Decatur, Georgia Organizations Australia * Australian Singi ...
. The ASC CARD domain recruits pro-caspase-1 into the complex.
Caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
activates maturation of
proinflammatory cytokines An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include in ...
(
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
, IL-18).


IFI16 inflammasome

Like AIM2,
IFI16 Gamma-interferon-inducible protein Ifi-16 (Ifi-16) also known as interferon-inducible myeloid differentiation transcriptional activator is a protein that in humans is encoded by the ''IFI16'' gene. Function This gene encodes a member of the ...
(IFN-inducible protein 16) belongs to the PYHIN (pyrin and HIN domain-containing) family. IFI16 in humans, and IFI204 the mouse orthologue, play an important role in regulating the production of
IFN Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten thei ...
during both bacterial and viral infections. In contrast to AIM2, IFI16 is a nuclear DNA sensor. Following interaction with viral DNAs, IFI16 was shown to recruit
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
through interaction with ASC, resulting in cell death of CD4+ T cells in response to HIV infection.


Pyrin

Assembly of the pyrin inflammasome is triggered by bacterial toxins as well as effector proteins via the detection of pathogen-driven disturbances in
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...
dynamics. More specifically, pyrin detects inactivation of the
Rho GTPase The Rho family of GTPases is a family of small (~21 kDa) signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found ...
RHOA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
by these bacterial factors. Following detection of RHOA inactivation, pyrin interacts with ASC through its N-terminal PYD domain to induce activation of caspase-1.


Non-canonical inflammasomes

The non-canonical inflammasomes are independent of
caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
. In mice, the non-canonical inflammasome is dependent on caspase-11, whereas human non-canonical inflammasomes rely on
caspase 4 Caspase 4 is an enzyme that proteolytically cleaves other proteins at an aspartic acid residue (LEVD-), and belongs to a family of cysteine proteases called caspases. The function of caspase 4 is not fully known, but it is believed to be an inf ...
and caspase 5. All of these caspases are able to directly bind intracellular LPS and subsequently form macromolecular complexes mediating Gasdermin-D cleavage and induction of pyroptotic cell death. In addition, non-canonical inflammasomes may also indirectly activate the NLRP3 inflammasome by triggering potassium efflux through membrane pores formed by Gasdermin-D. The NLRP3 inflammasome can then mediate processing of pro-inflammatory
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s and result in release of
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
and IL-18 in response to non-canonical inflammasome activation.


Role in health


Role in innate immunity

As part of the
innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
, inflammasomes play an important role in the induction of inflammatory cascades and coordination of host defenses, both via the activation and secretion of pro-inflammatory
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s and the induction of a specialized form of immune-stimulatory programmed cell death termed
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
. Inflammasomes and their components can also be involved in
PANoptosis PANoptosis is an inflammatory cell death pathway. Consideration of the totality of biological effects from cell death in multiple studies has led to the conceptualization of PANoptosis, a unique innate immune inflammatory cell death pathway regulate ...
, a unique form of inflammatory cell death that cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. In addition to professional cells of the
innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
such as
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s, several studies described various
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
inflammasomes and highlighted their crucial role as a first line of defense. Considering the importance of epithelia as common pathogen entry sites as a result of their location at the interface to the environment, it seems intuitive that epithelial tissues do not merely fulfill a function as a physical barrier, but additionally initiate a defensive response upon initial contact with the
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...
. In agreement with this, different inflammasome components were found to be expressed in a variety of epithelial tissues. Expression of innate immune components at epithelial barriers furthermore facilitates pathogen detection given that expression of virulence factors and hence exposure of
PAMPs Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
is required for the breaching of these barriers during invasion, whereas these factors might be downregulated when the pathogen interacts with professional immune cells at later stages of infection. Epithelial inflammasomes have mainly been studied in the intestinal mucosa, but there is also evidence for inflammasomes in other types of epithelial such as the urinary bladder epithelium. While the murine caspase-11 is mainly expressed in
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s, human caspase-4 is also expressed at high levels in intestinal epithelial cells. Similar to what was observed for the epithelial NAIP/NLRC4 inflammasome, human epithelial cells were shown to undergo caspase-4-dependent, caspase-1-independent cell death and extrusion in response to infection with the enteropathogens such as ''Salmonella'', ''
Shigella flexneri ''Shigella flexneri'' is a species of Gram-negative bacteria in the genus ''Shigella'' that can cause diarrhea in humans. Several different serogroups of ''Shigella'' are described; ''S. flexneri'' belongs to group ''B''. ''S. flexneri'' infec ...
'' or ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
''. Furthermore, secretion of IL-18 could be triggered by cytosolic LPS in epithelial cells.


Role of epithelial inflammasome

Activation of epithelial inflammasomes in response to invading pathogens has important cell-autonomous effects on the infected cell itself as well as on its communication with other cell types on a local and global level. These downstream consequences of inflammasome activation can be divided into three categories, namely (1) death of the epithelial cell itself, (2) release of soluble pro-inflammatory molecules, and (3) effector cell recruitment and activation. In addition, epithelial inflammasome activation induces contraction of epithelial layers and prevents integrity loss at later stages of infection. In order to maintain the integrity of the epithelial barrier, cell death and subsequent extrusion of the infected cell have to occur in a coordinated manner to ensure sealing of the gap in the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
by neighboring cells. Epithelial cell death can be triggered in a direct, cell-autonomous manner by inflammasome activation itself, as well as by local recruitment of other death-inducing cell types, or global inflammation, resulting in increased epithelial turnover that removes both infected and uninfected cells. The most important consequence of epithelial cell death is the reduction of epithelial pathogen loads in order to maintain barrier integrity. Inflammasome activation is known to trigger cleavage, activation and secretion of pro-inflammatory
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
and IL-18, which then recruit different types of effector cells and coordinate the innate immune response. Expression of pro-IL-1β is dependent on Toll-like-receptor signaling, and hence intestinal epithelial cells produce very low levels of IL-1β themselves. Pro-IL-18, on the other hand, is constitutively expressed by different kinds of epithelial cells, and readily secreted upon inflammasome activation. The IL-18 secreted by the epithelium can induce production of IFN-γ by different cell types. Importantly, inflammasome-derived IL-18 is also involved in recruitment of natural killer (NK) cells, that play a crucial role at early stages of innate immune responses. Furthermore, IL-18 can also stimulate the effector functions of NK cells that accumulated at the site of infection. The activated NK cells can then help in restricting the pathogen loads and spread to systemic sites at later time points compared to epithelium-autonomous induction of cell death. Finally, NK cells also secrete IFN-γ in order to recruit other inflammatory cell types. In a study of
UPEC ''Escherichia coli'' ( Anglicized to ; commonly abbreviated ''E. coli'') is a gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms (endotherms). Most ''E. coli'' strains are harmless, bu ...
infection of the urinary bladder epithelium, epithelial cells were found to secrete IL-1β at high levels in response to bacterial infection. The study reported IL-1β secretion to be dependent on the NLRP3 inflammasome and caspase-1, and the secreted pro-inflammatory cytokine was required for recruitment of mast cells to the site of infection. The mast cells then induce a lytic form of cell death in the epithelium by secreting granules that are taken up by the epithelium. Besides NK cells and mast cells,
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s are other important innate immune effector cells that infiltrate the infected tissue after breaching of epithelial barriers by pathogens. Both IL-1β and IL-18 secreted in response to inflammasome activation are involved in the recruitment of neutrophils. Once they have reached the infected tissue, the neutrophils assist in immobilizing and eliminating the invading pathogens, whereby they either directly engulf or kill invading microbes. Furthermore, they secrete inflammatory mediators such as IFN-γ and IL-22. IFN-γ is known to drive activation of microbicidal capacity of mononuclear phagocytes. IL-22, on the other hand, will strengthen the epithelial barrier. Finally, neutrophils are responsible for the elimination of bacteria that are trapped within pyroptotic
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s.


Role in disease

Problems with regulating inflammasomes have been linked to several autoimmune diseases such as type I and type II diabetes, inflammatory bowel disease (IBD), gouty arthritis, multiple sclerosis, and vitiligo as well as auto-inflammatory disorders. Gain-of-function mutations in inflammasome components are also known to cause Cryopyrin-associated periodic syndrome (CAPS), a group of congenital diseases characterised by IL-1β-mediated systemic inflammation.


Clinical significance

There has been some progress in the development of NLRP3 inhibitors some include: dapansutrile, and diarylsulfonylurea MCC-950.


References


Further reading

* * * * * * * * * {{Inflammation Protein complexes Cytokines