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词条 Inflammasome
释义

  1. History

  2. Function

  3. Inflammatory cascade

  4. NLR-subset inflammasomes

      NLRP1    Structure    Activation    NLRP3   Structure  Activation  NLRC4   Structure    Activation    The Adaptor ASC  

  5. AIM2

      Structure    Function  

  6. Dysregulated inflammasome activity

  7. References

  8. Further reading

The inflammasome is a multiprotein oligomer responsible for the activation of inflammatory responses.[1] The inflammasome promotes the maturation and secretion of pro-inflammatory cytokines Interleukin 1β (IL-1β) and Interleukin 18 (IL-18).[2] The secretion of these cytokines results in pyroptosis, a form of programmed pro-inflammatory cell death distinct from apoptosis.[3] In the case of dysregulation of the inflammasome, an assortment of major diseases may arise.[4] 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.[5] 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.[6][7]

History

The inflammasome was discovered by the team of Dr. Jürg Tschopp, at the University of Lausanne, in 2002.[2][8] Tschopp and team were able to articulate the inflammasome's role in diseases such as gout and type 2 diabetes.[8] They found that a variety of danger signals could provoke a response from an inflammasome including viral DNA, muramyl dipeptide (MDP), asbestos, and silica.[8] Tschopp and his colleagues found a connection between metabolic syndrome and NLRP3, a subset type of inflammasome.[8] Within their research on NLRP3, they were able to show that when NLRP3 is inhibited, an immunosuppressive behavior of type I interferon was exhibited.[8] Ultimately, the work of Dr. Tschopp and his team led to the research and eventual treatments of many major diseases and ailments.[8]

Function

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.[2] 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.[9] 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.[10]

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 (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.[11] 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,[2] cleavage of pro-IL-18 into IL-18 to induce IFN-γ secretion and natural killer cell activation,[12] cleavage and inactivation of IL-33,[13] DNA fragmentation and cell pore formation,[14] inhibition of glycolytic enzymes,[15] activation of lipid biosynthesis[16] and secretion of tissue-repair mediators such as pro-IL-1α.[17] Additionally, AIM2 contains a HIN200 domain which senses and binds foreign cytoplasmic dsDNA[18] and activates NF-κB,[9] 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 (NBD) which is bound by ribonucleotide-phosphates (rNTP) and is important for self-oligomerization.[19] 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 IPAF/NLRC4 have been identified in microglial cells.[20]

NLRP1

See NLRP1 for gene information

Structure

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.

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.[21] NLRP1 has been shown to confer macrophage sensitivity to anthrax lethal toxin (LT), suggesting the role of bacterial toxins in inducing inflammasome formation.[22]

NLRP1 activity is regulated by anti-apoptotic proteins Bcl-2 and Bcl-x(L) which, in resting cells, associate with and inhibit NLRP1 activity.[23]

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.[24]

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,[25] viruses e.g. influenza A,[26] HCV[27] and bacteria e.g. Neisseria gonorrhoeae,[28] bacterial toxins e.g. nigericin and maitotoxin,[1] liposomes,[29] urban particulate matter,[30] and most notably, crystallized endogenous molecules. Cholesterol crystals and monosodium urate (MSU) crystals increase NLRP3-induced IL-1β-production[31][32] 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 titanium dioxide, silicon dioxide and asbestos trigger the inflammasome-response.[33] 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.[24] Evidence indicates that NLRP3 inflammasome activation is involved in sleep regulation.[34]

NLRC4

See NLRC4 for gene information

Structure

NLRC4 (also known as IPAF) 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 involved in host defense.[35] NLRC4 is activated by bacteria, a number of which have been identified using murine macrophage culture studies: Salmonella typhimurium,[36] Legionella pneumophila,[37] and Pseudomonas aeruginosa.[38] 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.[39] ASC is required for activation of this inflammasome in some instances.[35]

Palmitate has been shown experimentally to induce the NLRC4 inflammasome without any bacteria present. This may give insight to other functions the inflammasome may have in the immune system, and also suggests that the inflammasome can respond to more than just bacteria. The NLRC4 inflammasome is regulated by cyclic adenosine monophosphate (cAMP).[35]

The Adaptor ASC

Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC or Pycard) plays a key role in activation of the inflammasome.[4] ASC helps recruit caspase-1 to associate with NLRs in the inflammasome complex.[40]

ASC also has duties independent of the inflammasome as it has been shown to be required for MHC class II to present antigenic peptides in dendritic cells.[4]

AIM2

Main article: AIM2

AIM2 is an acronym for absent in melanoma 2, and is sometimes also referred to as Interferon-inducible protein.{{citation needed|date=November 2015}}

Structure

AIM2 is a 343 amino acid non-NLR family protein with pyrin (DAPIN) and a HIN-200 domains,{{technical statement|date=November 2015}}[41] the former of which is activated in AIM2 by dsDNA.[42]

Function

AIM2 is referred to as the DNA inflammasome for its ability to detect foreign dsDNA, using a HIN200 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) domain (encoded by IFI16) attached to a PYD, which it uses to recruit the adaptor protein ASC during inflammasome formation.[43][44][45] AIM2 binds dsDNA with its C-terminal domain.[43][44][45]

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 (IL-1b, IL-18).

AIM2 is activated by viral dsDNA, bacterial dsDNA and also aberrant host dsDNA.[45][46] Activation of the AIM2 is supposed to play role in autoimmune responses during the autoimmune disease systematic lupus erythematosus.

AIM2 inflammasome is also activated by pharmacological disruption of nuclear envelope integrity.[47]

Dysregulated inflammasome activity

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.[4][48] These diseases and disorders have been connected to too much or too little secretion of the pro-inflammatory cytokines that the inflammasome is responsible for. Mutations or mistakes by the adaptive immune system (mistaking self as foreign/a danger signal) may be to blame for the dysregulation of the inflammasome.[49]

References

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43. ^1 {{cite journal |vauthors=Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G | title = An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome | journal = Nat. Immunol. | volume = 10 | issue = 3 | pages = 266–72 |date=March 2009 | pmid = 19158679 | doi = 10.1038/ni.1702 }}
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Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Jin T, Xiao TS | title = Activation and assembly of the inflammasomes through conserved protein domain families | journal = Apoptosis | volume = 20 | issue = 2 | pages = 151–6 | date = February 2015 | pmid = 25398536 | pmc = 4364414 | doi = 10.1007/s10495-014-1053-5 }}
  • {{cite journal | vauthors = Lu A, Wu H | title = Structural mechanisms of inflammasome assembly | journal = The FEBS Journal | volume = 282 | issue = 3 | pages = 435–44 | date = February 2015 | pmid = 25354325 | doi = 10.1111/febs.13133 | department = review }}
  • {{cite journal | vauthors = Shaw N, Liu ZJ | title = Role of the HIN domain in regulation of innate immune responses | journal = Molecular and Cellular Biology | volume = 34 | issue = 1 | pages = 2–15 | date = January 2014 | pmid = 24164899 | pmc = 3911281 | doi = 10.1128/MCB.00857-13 }}
  • {{cite journal | vauthors = Walsh JG, Muruve DA, Power C | title = Inflammasomes in the CNS | journal = Nature Reviews. Neuroscience | volume = 15 | issue = 2 | pages = 84–97 | date = February 2014 | pmid = 24399084| pmc = | doi = 10.1038/nrn3638 | department = review }}
  • {{cite journal | vauthors = Schroder K, Tschopp J | title = The inflammasomes | journal = Cell | volume = 140 | issue = 6 | pages = 821–32 | date = March 2010 | pmid = 20303873| pmc = | doi = 10.1016/j.cell.2010.01.040 | department = review }}
  • {{cite journal | vauthors = Jha S, Ting JP | title = Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases | journal = Journal of Immunology | volume = 183 | issue = 12 | pages = 7623–9 | date = December 2009 | pmid = 20007570 | pmc = 3666034 | doi = 10.4049/jimmunol.0902425 }}
  • {{cite journal | vauthors = Stutz A, Golenbock DT, Latz E | title = Inflammasomes: too big to miss | journal = The Journal of Clinical Investigation | volume = 119 | issue = 12 | pages = 3502–11 | date = December 2009 | pmid = 19955661 | pmc = 2786809 | doi = 10.1172/JCI40599 }}
  • {{cite journal | vauthors = Fink SL, Cookson BT | title = Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells | journal = Infection and Immunity | volume = 73 | issue = 4 | pages = 1907–16 | date = April 2005 | pmid = 15784530 | pmc = 1087413 | doi = 10.1128/IAI.73.4.1907-1916.2005 }}
  • {{cite journal | vauthors = Martinon F, Tschopp J | title = NLRs join TLRs as innate sensors of pathogens | journal = Trends in Immunology | volume = 26 | issue = 8 | pages = 447–54 | date = August 2005 | pmid = 15967716 | doi = 10.1016/j.it.2005.06.004 | department = review }}
{{refend}}{{Inflammation}}

2 : Protein complexes|Cytokines
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