Inflammasome structure

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses.[1][2] Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D.[2][3] The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane.[2] Additionally, inflammasomes can be incorporated into larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.[4]

Inflammasome activation is initiated by different kinds of cytosolic pattern recognition receptors (PRRs) that respond to either microbe-derived pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) generated by the host cell.[5] PRRs 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.[2] 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 via its CARD domain and activates the effector caspase through proteolytic cleavage.[2] The activated caspase-1 finally cleaves the immature pro-inflammatory cytokines pro-IL-1β and pro-IL-18, as well as gasdermin D, which are responsible for inflammatory signaling and pyroptotic cell death, respectively.[2] In addition to these so-called canonical inflammasomes, different studies also described non-canonical inflammasome complexes that act independently of caspase-1. In mice, the non-canonical inflammasome is activated by direct sensing of cytosolic bacterial lipopolysaccharide (LPS) by caspase-11, which subsequently induces pyroptotic cell death.[2] In human cells, the corresponding caspases of the non-canonical inflammasome are caspase 4 and caspase 5.[2]

Traditionally, inflammasomes have mainly been studied in professional immune cells of the innate immune system, such as macrophages. More recent studies, however, indicate high levels of inflammasome component expression in epithelial barrier tissues, where they have been shown to represent an important first line of defense.[5]

In the case of dysregulation of inflammasome activation, an assortment of major diseases, such as cancer, autoimmune, metabolic and neurodegenerative diseases may arise.[2][6]

Discovery

The inflammasome was discovered by the team of Jürg Tschopp, at the University of Lausanne, in 2002.[3][7] In 2002, it was first reported by Martinon et al.[3] that a subset of NLRs named NLRP1 were able to assemble and oligomerize into a common structure in vitro which collectively activated the caspase-1 cascade, thereby leading to the production of pro-inflammatory cytokines especially IL-1β and IL-18. This NLRP1 multi-molecular complex was dubbed the ‘inflammasome’, which spurred much interest in the following years. During that time, several other inflammasomes were discovered, two of which are also NLR subsets—NLRP3 and NLRC4. The physiological relevance of the inflammasome was then found in 2006 when three teams were able to articulate the inflammasome's role in diseases such as infection, exposure to toxins, gout and type 2 diabetes.[8][9][10][7] A variety of danger signals were found that could provoke a response from an inflammasome including viral DNA, muramyl dipeptide (MDP), asbestos, and silica.[7] Additional connections were also found between metabolic syndrome and NLRP3, a subset type of inflammasome.[7] Ultimately, the work on inflammasomes led to the current research field, where disease mechanisms and treatments are being investigated.[7]

In addition to NLR proteins, other PRRs can form inflammasomes. In 2009, Hornung et al.[11] 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.[12]

Inflammation activation

The inflammasome activates a pyroptotic inflammatory cascade.[13] 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.[14] 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-1β at Asp116 into IL-1β,[3] 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, an immunostimulatory form of programmed cell death in which the cell releases its cytoplasmic content to induce pro-inflammatory signaling.[2][15] IL-1β and IL-18 released following inflammasome activation were found to induce IFN-γ secretion and natural killer cell activation,[16] cleavage and inactivation of IL-33,[17] DNA fragmentation and cell pore formation,[18] inhibition of glycolytic enzymes,[19] activation of lipid biosynthesis[20] and secretion of tissue-repair mediators such as pro-IL-1α.[21] Additionally, AIM2 contains a HIN200 domain which senses and binds foreign cytoplasmic dsDNA[22] and activates NF-κB,[11] a role that is crucial in bacterial and viral infection.

Inflammasome family

NLRP1, NLRP3, NLRP6 and NLRC4 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.[23] The second is a C-terminal 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.[24]

Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC or Pycard) plays a key role in activation of the inflammasome.[6] ASC helps recruit caspase-1 to associate with NLRs in the inflammasome complex via its CARD domain.[25]

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.[6]

NLRP1 inflammasome

In addition to NOD and LRR, NLRP1 contains at its N-terminal a pyrin domain (PYD) and at its C-terminus 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.[2] 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.

NLRP1B in mice and NLRP2 in rats were found to be responsive to Bacillus anthracis lethal toxin.[2] The B. anthracis lethal factor proteolytically cleaves NLRP1B, which leads to ubiquitination of the receptor and targeting for degradation by the proteasome. 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.[5] So far, this activation mechanism depending on degradation by the proteasome machinery is unique among inflammasomes.[5]

NLRP1 activity is regulated by anti-apoptotic proteins Bcl-2 and Bcl-x(L) which, in resting cells, associate with and inhibit NLRP1 activity.[26]

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.[27]

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 or asbestos, calcium influx, mitochondrial reactive oxygen species (ROS), and extracellular ATP.[2][28] The NLRP3 inflammasome was also found to respond to PAMPs of different pathogens, such as viruses, e.g. influenza A,[29] bacteria, e.g. Neisseria gonorrhoeae,[30] and bacterial toxins e.g. nigericin and maitotoxin.[1]

All NLRP3 activators induce cytosolic potassium efflux from cells and a sufficiently low cytosolic potassium concentration is capable of triggering NLRP3 activation in the absence other activators.[2] Hence, the downstream point where all the different NLRP3 stimuli converge appears to be low intracellular potassium concentrations.[2] NLRP3 inflammasome activation by cholesterol crystals and 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 in the cell. It has also been proven that inorganic particles like titanium dioxide, silicon dioxide and asbestos can trigger activation of the inflammasome.[33] One study even indicates that NLRP3 inflammasome activation is involved in sleep regulation.[34] Recent studies show that NLRP3 inflammasome-mediated neuroinflammation is involved in secondary brain injury after intracerebral hemorrhage.[35]

The major endogenous product of lipid peroxidation, 4-hydroxynonenal, directly bound to NLRP3 and inhibited the NLRP3 inflammasome activation independently of Nrf2 and NF-κB signaling[36]

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.[37] In mice, NAIPs are activated by binding to the bacterial PAMPs in the cytosol, given by the rod (NAIP2) and needle (NAIP1) components of the bacterial type-3 secretion system (T3SS), as well as flagellin, the molecular building block of flagella (NAIP5 and 6). In humans, there is only one NAIP, and it responds only to needle component.[2][38] 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.[38]

Palmitate has been shown experimentally to induce the NLRC4 inflammasome without any bacteria present.[37]

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 and Citrobacter rodentium.[39][40] 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.[39][40] This process is also referred to as epithelial cell extrusion, 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 (CRC), by triggering the removal of tumor-initiating cells.[39]

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.[2] AIM2 is activated by viral dsDNA, bacterial dsDNA and also aberrant host dsDNA.,[41][42] and consequently it has been linked to different human diseases. For example autoinflammation in psoriasis disease was found to be connected to recognition of self-DNA by AIM2.[2] Furthermore, activation of the AIM2 is supposed to play role in autoimmune responses during the autoimmune disease systematic lupus erythematosus. The AIM2 inflammasome is also activated by pharmacological disruption of nuclear envelope integrity.[43] AIM2 binds dsDNA with its C-terminal HIN-200 domain.[44][22][41] The PYDdomain of AIM2 homotypically interacts by PYD-PYD interactions with ASC. The ASC CARD domain recruits pro-caspase-1 into the complex. Caspase-1 activates maturation of proinflammatory cytokines (IL-1β, IL-18).

IFI16 inflammasome

Like AIM2, IFI16 (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 during both bacterial and viral infections.[2] In contrast to AIM2, IFI16 is a nuclear DNA sensor.[5] Following interaction with viral DNAs, IFI16 was shown to recruit caspase-1 through interaction with ASC, resulting in cell death of CD4+ T cells in response to HIV infection.[2]

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 dynamics.[2] More specifically, pyrin detects inactivation of the Rho GTPase RHOA by these bacterial factors.[2] Following detection of RHOA inactivation, pyrin interacts with ASC through its N-terminal PYD domain to induce activation of caspase-1.[2]

Non-canonical inflammasomes

The non-canonical inflammasomes are independent of caspase-1. In mice, the non-canonical inflammasome is dependent on caspase-11, whereas human non-canonical inflammasomes rely on caspase 4 and caspase 5.[2] 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.[5]

In addition, non-canonical inflammasomes may also indirectly activate the NLRP3 inflammasome by triggering potassium efflux through membrane pores formed by Gasdermin-D.[5] The NLRP3 inflammasome can then mediate processing of pro-inflammatory cytokines and result in release of IL-1β and IL-18 in response to non-canonical inflammasome activation.[2]

Role in health

Role in innate immunity

As part of the innate immune system, 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 cytokines and the induction of a specialized form of immune-stimulatory programmed cell death termed pyroptosis.[2] Inflammasomes and their components can also be involved in PANoptosis, a unique form of inflammatory cell death that cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone.[45]

In addition to professional cells of the innate immune system such as macrophages, several studies described various epithelial inflammasomes and highlighted their crucial role as a first line of defense.[5][39] 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 agreement with this, different inflammasome components were found to be expressed in a variety of epithelial tissues.[5][39] Expression of innate immune components at epithelial barriers furthermore facilitates pathogen detection given that expression of virulence factors and hence exposure of PAMPs 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.[40] 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.[40]

While the murine caspase-11 is mainly expressed in macrophages, human caspase-4 is also expressed at high levels in intestinal epithelial cells.[39] 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 or Escherichia coli.[39] Furthermore, secretion of IL-18 could be triggered by cytosolic LPS in epithelial cells.[39]

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.[40] 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.[40] In addition, epithelial inflammasome activation induces contraction of epithelial layers[46] and prevents integrity loss at later stages of infection.[47]

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 by neighboring cells.[40] 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.[40] The most important consequence of epithelial cell death is the reduction of epithelial pathogen loads in order to maintain barrier integrity.[40]

Inflammasome activation is known to trigger cleavage, activation and secretion of pro-inflammatory IL-1β and IL-18,[2] which then recruit different types of effector cells and coordinate the innate immune response.[40] 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.[40] 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.[40] Furthermore, IL-18 can also stimulate the effector functions of NK cells that accumulated at the site of infection.[40] 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.[40] Finally, NK cells also secrete IFN-γ in order to recruit other inflammatory cell types.[40]

In a study of UPEC 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.[40]

Besides NK cells and mast cells, neutrophils 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.[40] 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.[40] 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.[40] Finally, neutrophils are responsible for the elimination of bacteria that are trapped within pyroptotic macrophages.[40]

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.[6][48]

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.[49][50]

References

  1. ^ a b Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. (July 2004). "Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf". Nature. 430 (6996): 213–218. Bibcode:2004Natur.430..213M. doi:10.1038/nature02664. PMID 15190255. S2CID 4317409.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Broz P, Dixit VM (July 2016). "Inflammasomes: mechanism of assembly, regulation and signalling". Nature Reviews. Immunology. 16 (7): 407–420. doi:10.1038/nri.2016.58. PMID 27291964. S2CID 32414010.
  3. ^ a b c d Martinon F, Burns K, Tschopp J (August 2002). "The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta". Molecular Cell. 10 (2): 417–426. doi:10.1016/S1097-2765(02)00599-3. PMID 12191486.
  4. ^ "The PANoptosome: A new frontier in innate immune responses".
  5. ^ a b c d e f g h i Winsor N, Krustev C, Bruce J, Philpott DJ, Girardin SE (November 2019). "Canonical and noncanonical inflammasomes in intestinal epithelial cells". Cellular Microbiology. 21 (11): e13079. doi:10.1111/cmi.13079. PMID 31265745. S2CID 195786609.
  6. ^ a b c d Ippagunta SK, Malireddi RK, Shaw PJ, Neale GA, Vande Walle L, Green DR, et al. (September 2011). "The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization". Nature Immunology. 12 (10): 1010–1016. doi:10.1038/ni.2095. PMC 3178750. PMID 21892172.
  7. ^ a b c d e Dagenais M, Skeldon A, Saleh M (January 2012). "The inflammasome: in memory of Dr. Jurg Tschopp". Cell Death and Differentiation. 19 (1): 5–12. doi:10.1038/cdd.2011.159. PMC 3252823. PMID 22075986.
  8. ^ Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monaco DM, Dixit VM (Mar 2006). "Cryopyrin activates the inflammasome in response to toxins and ATP". Nature. 440 (7081): 228–232. Bibcode:2006Natur.440..228M. doi:10.1038/nature04515. PMID 16407890. S2CID 4373339.
  9. ^ Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (Mar 2006). "Gout-associated uric acid crystals activate the NALP3 inflammasome". Nature. 440 (7081): 237–241. Bibcode:2006Natur.440..237M. doi:10.1038/nature04516. PMID 16407889. S2CID 2692522.
  10. ^ Kanneganti TD, Ozone N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Nunez G (Mar 2006). "Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3". Nature. 440 (7081): 233–236. Bibcode:2006Natur.440..233K. doi:10.1038/nature04517. hdl:2027.42/62569. PMID 16407888. S2CID 4345315.
  11. ^ a b Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. (March 2009). "AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC". Nature. 458 (7237): 514–518. Bibcode:2009Natur.458..514H. doi:10.1038/nature07725. PMC 2726264. PMID 19158675.
  12. ^ Cai X, Chen J, Xu H, Liu S, Jiang QX, Halfmann R, Chen ZJ (March 2014). "Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation". Cell. 156 (6): 1207–1222. doi:10.1016/j.cell.2014.01.063. PMC 4034535. PMID 24630723.
  13. ^ Bergsbaken T, Fink SL, Cookson BT (February 2009). "Pyroptosis: host cell death and inflammation". Nature Reviews. Microbiology. 7 (2): 99–109. doi:10.1038/nrmicro2070. PMC 2910423. PMID 19148178.
  14. ^ Yamin TT, Ayala JM, Miller DK (May 1996). "Activation of the native 45-kDa precursor form of interleukin-1-converting enzyme". The Journal of Biological Chemistry. 271 (22): 13273–13282. doi:10.1074/jbc.271.22.13273. PMID 8662843.
  15. ^ Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, et al. (May 2021). "Gasdermin D pore structure reveals preferential release of mature interleukin-1". Nature. 593 (7860): 607–611. Bibcode:2021Natur.593..607X. doi:10.1038/s41586-021-03478-3. PMC 8588876. PMID 33883744. S2CID 233351704.
  16. ^ Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, et al. (January 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. S2CID 85955985.
  17. ^ Cayrol C, Girard JP (June 2009). "The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1". Proceedings of the National Academy of Sciences of the United States of America. 106 (22): 9021–9026. Bibcode:2009PNAS..106.9021C. doi:10.1073/pnas.0812690106. PMC 2690027. PMID 19439663.
  18. ^ Fink SL, Cookson BT (November 2006). "Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages". Cellular Microbiology. 8 (11): 1812–1825. doi:10.1111/j.1462-5822.2006.00751.x. PMID 16824040. S2CID 23338786.
  19. ^ Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M (December 2007). "The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock". The Journal of Biological Chemistry. 282 (50): 36321–36329. doi:10.1074/jbc.M708182200. PMID 17959595.
  20. ^ Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG (September 2006). "Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival". Cell. 126 (6): 1135–1145. doi:10.1016/j.cell.2006.07.033. PMID 16990137. S2CID 616037.
  21. ^ Keller M, Rüegg A, Werner S, Beer HD (March 2008). "Active caspase-1 is a regulator of unconventional protein secretion". Cell. 132 (5): 818–831. doi:10.1016/j.cell.2007.12.040. PMID 18329368. S2CID 17330211.
  22. ^ a b 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): 509–513. Bibcode:2009Natur.458..509F. doi:10.1038/nature07710. PMC 2862225. PMID 19158676.
  23. ^ Ye Z, Lich JD, Moore CB, Duncan JA, Williams KL, Ting JP (March 2008). "ATP binding by monarch-1/NLRP12 is critical for its inhibitory function". Molecular and Cellular Biology. 28 (5): 1841–1850. doi:10.1128/MCB.01468-07. PMC 2258772. PMID 18160710.
  24. ^ Jamilloux Y, Pierini R, Querenet M, Juruj C, Fauchais AL, Jauberteau MO, et al. (April 2013). "Inflammasome activation restricts Legionella pneumophila replication in primary microglial cells through flagellin detection". Glia. 61 (4): 539–549. doi:10.1002/glia.22454. PMID 23355222. S2CID 28910610.
  25. ^ Kanneganti TD, Lamkanfi M, Núñez G (October 2007). "Intracellular NOD-like receptors in host defense and disease". Immunity. 27 (4): 549–559. doi:10.1016/j.immuni.2007.10.002. PMID 17967410.
  26. ^ Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, et al. (April 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. S2CID 18347164.
  27. ^ Stutz A, Golenbock DT, Latz E (December 2009). "Inflammasomes: too big to miss". The Journal of Clinical Investigation. 119 (12): 3502–3511. doi:10.1172/JCI40599. PMC 2786809. PMID 19955661.
  28. ^ Crowley SM, Knodler LA, Vallance BA (2016). "Salmonella and the Inflammasome: Battle for Intracellular Dominance". In Backert S (ed.). Inflammasome Signaling and Bacterial Infections. Current Topics in Microbiology and Immunology. Vol. 397. Springer International Publishing. pp. 43–67. doi:10.1007/978-3-319-41171-2_3. ISBN 978-3-319-41170-5. PMID 27460804.
  29. ^ Thomas PG, Dash P, Aldridge JR, Ellebedy AH, Reynolds C, Funk AJ, et al. (April 2009). "The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1". Immunity. 30 (4): 566–575. doi:10.1016/j.immuni.2009.02.006. PMC 2765464. PMID 19362023.
  30. ^ Duncan JA, Gao X, Huang MT, O'Connor BP, Thomas CE, Willingham SB, et al. (May 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): 6460–6469. doi:10.4049/jimmunol.0802696. PMC 2722440. PMID 19414800.
  31. ^ Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J (March 2006). "Gout-associated uric acid crystals activate the NALP3 inflammasome". Nature. 440 (7081): 237–241. Bibcode:2006Natur.440..237M. doi:10.1038/nature04516. PMID 16407889.
  32. ^ Jamilloux Y, Sève P, Henry T (November 2014). "[Inflammasomes in human diseases]". La Revue de Médecine Interne. 35 (11): 730–741. doi:10.1016/j.revmed.2014.04.017. PMID 24907108.
  33. ^ Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, Couillin I, Tschopp J (November 2010). "Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β". Proceedings of the National Academy of Sciences of the United States of America. 107 (45): 19449–19454. Bibcode:2010PNAS..10719449Y. doi:10.1073/pnas.1008155107. PMC 2984140. PMID 20974980.
  34. ^ Zielinski MR, Gerashchenko D, Karpova SA, Konanki V, McCarley RW, Sutterwala FS, et al. (May 2017). "The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide". Brain, Behavior, and Immunity. 62: 137–150. doi:10.1016/j.bbi.2017.01.012. PMC 5373953. PMID 28109896.
  35. ^ Ren H, Han R, Chen X, Liu X, Wan J, Wang L, et al. (September 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". Journal of Cerebral Blood Flow and Metabolism. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC 7446569. PMID 32423330. S2CID 218689863.
  36. ^ Hsu CG, Chávez CL, Zhang C, Sowden M, Yan C, Berk BC (September 2022). "The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis". Cell Death & Differentiation. 29 (9): 1790–1803. doi:10.1038/s41418-022-00966-5. PMC 9433404. PMID 35264781.
  37. ^ a b Liu L, Chan C (February 2014). "IPAF inflammasome is involved in interleukin-1β production from astrocytes, induced by palmitate; implications for Alzheimer's Disease". Neurobiology of Aging. 35 (2): 309–321. doi:10.1016/j.neurobiolaging.2013.08.016. PMC 3832124. PMID 24054992.
  38. ^ a b Zhao Y, Shao F (May 2015). "The NAIP-NLRC4 inflammasome in innate immune detection of bacterial flagellin and type III secretion apparatus". Immunological Reviews. 265 (1): 85–102. doi:10.1111/imr.12293. PMID 25879286. S2CID 24423221.
  39. ^ a b c d e f g h Sellin ME, Maslowski KM, Maloy KJ, Hardt WD (August 2015). "Inflammasomes of the intestinal epithelium". Trends in Immunology. 36 (8): 442–450. doi:10.1016/j.it.2015.06.002. PMID 26166583.
  40. ^ a b c d e f g h i j k l m n o p q r s t Sellin ME, Müller AA, Hardt WD (January 2018). "Consequences of Epithelial Inflammasome Activation by Bacterial Pathogens". Journal of Molecular Biology. Mechanisms of Inflammasome Activation. 430 (2): 193–206. doi:10.1016/j.jmb.2017.03.031. PMID 28454742.
  41. ^ a b Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, et al. (February 2009). "HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA". Science. 323 (5917): 1057–1060. Bibcode:2009Sci...323.1057R. doi:10.1126/science.1169841. PMID 19131592. S2CID 43712804.
  42. ^ Muruve DA, Pétrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. (March 2008). "The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response". Nature. 452 (7183): 103–107. Bibcode:2008Natur.452..103M. doi:10.1038/nature06664. PMID 18288107. S2CID 205212334.
  43. ^ Di Micco A, Frera G, Lugrin J, Jamilloux Y, Hsu ET, Tardivel A, et al. (August 2016). "AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity". Proceedings of the National Academy of Sciences of the United States of America. 113 (32): E4671–E4680. Bibcode:2016PNAS..113E4671D. doi:10.1073/pnas.1602419113. PMC 4987819. PMID 27462105.
  44. ^ Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, et al. (March 2009). "An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome". Nature Immunology. 10 (3): 266–272. doi:10.1038/ni.1702. PMID 19158679. S2CID 5597950.
  45. ^ "ZBP1 links interferon treatment and dangerous inflammatory cell death during COVID-19". www.stjude.org. Retrieved 2022-06-09.
  46. ^ Samperio Ventayol P, Geiser P, Di Martino ML, Florbrant A, Fattinger SA, Walder N, et al. (April 2021). "Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers". Proceedings of the National Academy of Sciences of the United States of America. 118 (16): e2013963118. Bibcode:2021PNAS..11813963S. doi:10.1073/pnas.2013963118. PMC 8072224. PMID 33846244.
  47. ^ Fattinger SA, Geiser P, Samperio Ventayol P, Di Martino ML, Furter M, Felmy B, et al. (May 2021). "Epithelium-autonomous NAIP/NLRC4 prevents TNF-driven inflammatory destruction of the gut epithelial barrier in Salmonella-infected mice". Mucosal Immunology. 14 (3): 615–629. doi:10.1038/s41385-021-00381-y. PMC 8075861. PMID 33731826.
  48. ^ So A, Busso N (October 2014). "The concept of the inflammasome and its rheumatologic implications". Joint Bone Spine. 81 (5): 398–402. doi:10.1016/j.jbspin.2014.02.009. PMID 24703401.
  49. ^ "Dapansutrile" (PDF). Alzheimer's Drug Discovery Foundation. November 2019. Archived (PDF) from the original on 2021-08-22. Retrieved 2020-12-17.
  50. ^ Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. (March 2015). "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases". Nature Medicine. 21 (3): 248–255. doi:10.1038/nm.3806. PMC 4392179. PMID 25686105.

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