Inflammasome

The inflammasome is a multiprotein oligomer consisting of caspase 1, PYCARD, NALP and sometimes caspase 5 (also known as caspase 11 or ICH-3). 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 (IL-1β) and Interleukin 18 (IL-18).[1]

The inflammasome is responsible for activation of inflammatory processes,[2] and has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis.[3]

History

The inflammasome was discovered by the team of Prof. Jürg Tschopp, at the University of Lausanne, in 2002.[1]

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.[1] 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.[4] 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.[5]

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.[6] 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,[1] cleavage of pro-IL-18 into IL-18 to induce IFN-γ secretion and natural killer cell activation,[7] cleavage and inactivation of IL-33,[8] DNA fragmentation and cell pore formation,[9] inhibition of glycolytic enzymes,[10] activation of lipid biosynthesis[11] and secretion of tissue-repair mediators such as pro-IL-1α.[12] Additionally, AIM2 contains a HIN200 domain which senses and binds foreign cytoplasmic dsDNA[13] and activates NF-κB,[4] 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 to by ribonucleotide-phosphates (rNTP) and is important for self-oligomerization.[14] 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

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.[15] NLRP1 has been shown to confer macrophage sensitivity to anthrax lethal toxin (LT), suggesting the role of bacterial toxins in inducing inflammasome formation.[16]

NLRP1 activity is regulated by anti-apoptotic proteins Bcl-2 and Bcl-x(L) which, in resting cells, associate with and inhibit NLRP1 activity.[17]

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.[18]

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,[19] viruses e.g. influenza A[20] and Neisseria gonorrhoeae,[21] bacterial toxins e.g. nigericin and maitotoxin,[2] liposomes,[22] urban particulate matter,[23] and most notably, crystallized endogenous molecules. Cholesterol crystals and monosodium urate (MSU) crystals increase NLRP3-induced IL-1β-production[24] 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.[25] 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.[18]

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 activated by bacteria, a number of which have been identified using murine macrophage culture studies: Salmonella typhimurium,[26] Legionella pneumophila[27] and Pseudomonas aeruginosa.[28] 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.[29]

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 (DAPIN) and a HIN-200 domains,[30] the former of which is activated in AIM2 by dsDNA.[31]

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.[32][33][34] AIM2 binds dsDNA with its C-terminal domain.[32][33][34] 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.[34][35] Activation of the AIM2 is supposed to play role in autoimmune responses during the autoimmune disease systematic lupus erythematosus.

Further reading

References

  1. 1 2 3 4 Martinon F, Burns K, Tschopp J (2002). "The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.". Mol Cell 10 (2): 417–26. doi:10.1016/S1097-2765(02)00599-3. PMID 12191486.
  2. 1 2 Mariathasan S, Newton K, Monack D, Vucic D, French D, Lee W, Roose-Girma M, Erickson S, Dixit V (2004). "Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf". Nature 430 (6996): 213–8. doi:10.1038/nature02664. PMID 15190255.
  3. ↑ Fink SL, Cookson BT (2005). "Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells" (review). Infect. Immun. 73 (4, April): 1907–16. doi:10.1128/IAI.73.4.1907-1916.2005. PMC 1087413. PMID 15784530.
  4. 1 2 Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA. (2009). "AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.". Nature 458 (7237): 514–8. doi:10.1038/nature07725. PMC 2726264. PMID 19158675.
  5. ↑ Cai X, Chen J, Xu H, Liu S, Jiang QX, Halfmann R, Chen ZJ (2014). "Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation.". Cell 156 (6): 1207–22. doi:10.1016/j.cell.2014.01.063. PMID 24630723.
  6. ↑ Yamin TT, Ayala JM, Miller DK. (1996). "Activation of the native 45-kDa precursor form of interleukin-1 converting enzyme.". J Biol Chem 271 (22): 13273–13282. doi:10.1074/jbc.271.22.13273. PMID 8662843.
  7. ↑ Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS. (1997). "Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.". Science 275 (5297): 206–209. doi:10.1126/science.275.5297.206. PMID 8999548.
  8. ↑ Cayrol C, Girard JP. (2009). "The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1.". Proc Natl Acad Sci U S A. 106 (22): 9021–6. doi:10.1073/pnas.0812690106. PMC 2690027. PMID 19439663.
  9. ↑ Fink SL, Cookson BT. (2006). "Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages.". Cell Microbiol. 8 (11): 1812–25. doi:10.1111/j.1462-5822.2006.00751.x. PMID 16824040.
  10. ↑ Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M. (2007). "The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock.". J Biol Chem. 282 (50): 36321–9. doi:10.1074/jbc.M708182200. PMID 17959595.
  11. ↑ Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG. (2006). "Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.". Cell 126 (6): 1135–45. doi:10.1016/j.cell.2006.07.033. PMID 16990137.
  12. ↑ Keller M, Rüegg A, Werner S, Beer HD. (2008). "Active caspase-1 is a regulator of unconventional protein secretion.". Cell 132 (5): 818–31. doi:10.1016/j.cell.2007.12.040. PMID 18329368.
  13. ↑ Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. (2009). "AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA.". Nature 458 (7237): 509–13. doi:10.1038/nature07710. PMC 2862225. PMID 19158676.
  14. ↑ Ye Z, Lich JD, Moore CB, Duncan JA, Williams KL, Ting JP. (2008). "ATP binding by monarch-1/NLRP12 is critical for its inhibitory function.". Mol Cell Biol. 28 (5): 1841–50. doi:10.1128/MCB.01468-07. PMC 2258772. PMID 18160710.
  15. ↑ Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. (2007). "Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation.". Mol Cell Biol. 25 (5): 713–24. doi:10.1016/j.molcel.2007.01.032. PMID 17349957.
  16. ↑ Boyden ED, Dietrich WF. (2006). "Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.". Nat. Genet. 38 (2): 240–4. doi:10.1038/ng1724. PMID 16429160.
  17. ↑ Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC. (2007). "Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1.". Cell 129 (1): 45–56. doi:10.1016/j.cell.2007.01.045. PMID 17418785.
  18. 1 2 Stutz A, Golenbock DT, Latz E. (2009). "Inflammasomes: too big to miss." (review). J Clin Invest 119 (12): 3502–3511. doi:10.1172/JCI40599. PMC 2786809. PMID 19955661.
  19. ↑ Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. (2007). "Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.". Nature 14 (9): 1583–9. doi:10.1038/sj.cdd.4402195. PMID 17599094.
  20. ↑ Thomas PG, Dash P, Aldridge JR Jr, Ellebedy AH, Reynolds C, Funk AJ, Martin WJ, Lamkanfi M, Webby RJ, Boyd KL, Doherty PC, Kanneganti TD. (2009). "The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.". Immunity 30 (4): 566–75. doi:10.1016/j.immuni.2009.02.006. PMC 2765464. PMID 19362023.
  21. ↑ Duncan JA, Gao X, Huang MT, O'Connor BP, Thomas CE, Willingham SB, Bergstralh DT, Jarvis GA, Sparling PF, Ting JP. (2009). "Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome.". Journal of Immunology 182 (10): 6460–9. doi:10.4049/jimmunol.0802696. PMC 2722440. PMID 19414800.
  22. ↑ Zhong Z, Zhai, Y, Liang S, Mori Y, Han R, Sutterwala FS & Qiao L. (2013). "TRPM2 links oxidative stress to NLRP3 inflammasome activation". Nature Communications 4 (1611). doi:10.1038/ncomms2608.
  23. ↑ Hirota JA, Hirota SA, Warner SM, Stefanowicz D, Shaheen F, Beck PL, Macdonald JA, Hackett TL, Sin DD, Van Eeden S, Knight DA. (2012). "The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter.". J Allergy Clin Immunol. 129 (4): 1116–25. doi:10.1016/j.jaci.2011.11.033. PMID 22227418.
  24. ↑ Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. (2006). "Gout-associated uric acid crystals activate the NALP3 inflammasome.". Nature 440 (7081): 237–41. doi:10.1038/nature04516. PMID 16407889.
  25. ↑ Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, Couillin I, Tschopp J. (Nov 2010). "Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β.". Proc Natl Acad Sci U S A 107 (45): 19449–19454. doi:10.1073/pnas.1008155107. PMC 2984140. PMID 20974980.
  26. ↑ Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galán JE. (2006). "Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis.". J Exp Med. 203 (6): 1407–12. doi:10.1084/jem.20060206. PMC 2118315. PMID 16717117.
  27. ↑ Amer A, Franchi L, Kanneganti TD, Body-Malapel M, Ozören N, Brady G, Meshinchi S, Jagirdar R, Gewirtz A, Akira S, Núñez G. (2006). "Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf.". J Biol Chem 281 (12): 35217–35223. doi:10.1074/jbc.M604933200. PMID 16984919.
  28. ↑ Franchi L, Stoolman J, Kanneganti TD, Verma A, Ramphal R, Núñez G. (2007). "Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation.". European Journal of Immunology 37 (11): 3030–9. doi:10.1002/eji.200737532. PMID 17935074.
  29. ↑ Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozören N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Núñez G. (2006). "Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.". Nat Immunol. 7 (6): 576–82. doi:10.1038/ni1346. PMID 16648852.
  30. ↑ Anon. (2015). "Entrez Gene: AIM2 absent in melanoma 2 [ Homo sapiens (human)], Gene ID: 9447 (updated on 8-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015.
  31. ↑ Lu A & Wu H (2015). "Structural mechanisms of inflammasome assembly" (review). FEBS J. 282 (3, February): 435–444. doi:10.1111/febs.13133. PMID 25354325. Retrieved 14 November 2015.
  32. 1 2 Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G (March 2009). "An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome". Nat. Immunol. 10 (3): 266–72. doi:10.1038/ni.1702. PMID 19158679.
  33. 1 2 Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES (March 2009). "AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA". Nature 458 (7237): 509–13. doi:10.1038/nature07710. PMC 2862225. PMID 19158676.
  34. 1 2 3 Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, Hardy LL, Garceau V, Sweet MJ, Ross IL, Hume DA, Stacey KJ (February 2009). "HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA". Science 323 (5917): 1057–60. doi:10.1126/science.1169841. PMID 19131592.
  35. ↑ Muruve DA, Pétrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, Parks RJ, Tschopp J (March 2008). "The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response". Nature 452 (7183): 103–7. doi:10.1038/nature06664. PMID 18288107.
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