Global InformationInflammasome information
Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death.[1][2] They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions.[1][2][3] Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD).[2][3][4] The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines.[2][5] Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.[4][6]
The germline-encoded PRRs that drive inflammasome formation consist of NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors), AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16), and pyrin.[2][7] Through their caspase activation and recruitment domain (CARD) or pyrin domain (PYD), the inflammasome receptors interact with the adaptor protein called apoptosis-associated speck like protein containing a CARD (also known as ASC or Pycard), which then recruits pro-caspase-1 via its CARD domain to activate inflammatory signaling and pyroptotic cell death.[2][8] Notably, the PYD of the adaptor protein ASC has been demonstrated to function as a prion-like domain, forming a self-perpetuating polymer when activated.[9] In addition to inflammasomes activating caspase-1, several studies also described non-canonical inflammasome complexes that act independent 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.[doi:10.1038/nri.2016.58] In human cells, the corresponding caspases of the non-canonical inflammasome are caspase 4 and caspase 5.[10][11][12][13][14]
Traditionally, inflammasomes have mainly been studied in professional innate immune cells, such as macrophages. However, recent studies indicate high levels of inflammasome component expression in epithelial barrier tissues, where they have been demonstrated to serve as an important first line of defense.[15] Moreover, the dysregulation of inflammasome activation can contribute to the pathology of several major diseases, including cancer, autoimmune disorders, inflammatory conditions, metabolic disorders, and neurodegenerative diseases.[2][16]
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- ^ a b c d e f g 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.
- ^ a b Broz, Petr; Monack, Denise M. (August 2013). "Newly described pattern recognition receptors team up against intracellular pathogens". Nature Reviews Immunology. 13 (8): 551–565. doi:10.1038/nri3479. ISSN 1474-1733. PMID 23846113.
- ^ a b Martinon, Fabio; Burns, Kimberly; Tschopp, Jürg (August 2002). "The Inflammasome". Molecular Cell. 10 (2): 417–426. doi:10.1016/S1097-2765(02)00599-3. PMID 12191486.
- ^ Fu, Jianing; Schroder, Kate; Wu, Hao (2024-02-19). "Mechanistic insights from inflammasome structures". Nature Reviews Immunology: 1–18. doi:10.1038/s41577-024-00995-w. ISSN 1474-1733. PMID 38374299.
- ^ Pandian, Nagakannan; Kanneganti, Thirumala-Devi (2022-11-01). "PANoptosis: A Unique Innate Immune Inflammatory Cell Death Modality". The Journal of Immunology. 209 (9): 1625–1633. doi:10.4049/jimmunol.2200508. ISSN 0022-1767. PMC 9586465. PMID 36253067.
- ^ Barnett, Katherine C.; Li, Sirui; Liang, Kaixin; Ting, Jenny P.-Y. (May 2023). "A 360° view of the inflammasome: Mechanisms of activation, cell death, and diseases". Cell. 186 (11): 2288–2312. doi:10.1016/j.cell.2023.04.025. PMC 10228754. PMID 37236155.
- ^ 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.
- ^ 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.
- ^ Kayagaki, Nobuhiko; Warming, Søren; Lamkanfi, Mohamed; Walle, Lieselotte Vande; Louie, Salina; Dong, Jennifer; Newton, Kim; Qu, Yan; Liu, Jinfeng; Heldens, Sherry; Zhang, Juan; Lee, Wyne P.; Roose-Girma, Merone; Dixit, Vishva M. (November 2011). "Non-canonical inflammasome activation targets caspase-11". Nature. 479 (7371): 117–121. Bibcode:2011Natur.479..117K. doi:10.1038/nature10558. ISSN 0028-0836. PMID 22002608.
- ^ Aachoui, Youssef; Leaf, Irina A.; Hagar, Jon A.; Fontana, Mary F.; Campos, Cristine G.; Zak, Daniel E.; Tan, Michael H.; Cotter, Peggy A.; Vance, Russell E.; Aderem, Alan; Miao, Edward A. (2013-02-22). "Caspase-11 Protects Against Bacteria That Escape the Vacuole". Science. 339 (6122): 975–978. Bibcode:2013Sci...339..975A. doi:10.1126/science.1230751. ISSN 0036-8075. PMC 3697099. PMID 23348507.
- ^ Casson, Cierra N.; Copenhaver, Alan M.; Zwack, Erin E.; Nguyen, Hieu T.; Strowig, Till; Javdan, Bahar; Bradley, William P.; Fung, Thomas C.; Flavell, Richard A.; Brodsky, Igor E.; Shin, Sunny (2013-06-06). Isberg, Ralph R. (ed.). "Caspase-11 Activation in Response to Bacterial Secretion Systems that Access the Host Cytosol". PLOS Pathogens. 9 (6): e1003400. doi:10.1371/journal.ppat.1003400. ISSN 1553-7374. PMC 3675167. PMID 23762026.
- ^ Shi, Jianjin; Zhao, Yue; Wang, Yupeng; Gao, Wenqing; Ding, Jingjin; Li, Peng; Hu, Liyan; Shao, Feng (October 2014). "Inflammatory caspases are innate immune receptors for intracellular LPS". Nature. 514 (7521): 187–192. Bibcode:2014Natur.514..187S. doi:10.1038/nature13683. ISSN 0028-0836. PMID 25119034.
- ^ Kayagaki, Nobuhiko; Stowe, Irma B.; Lee, Bettina L.; O’Rourke, Karen; Anderson, Keith; Warming, Søren; Cuellar, Trinna; Haley, Benjamin; Roose-Girma, Merone; Phung, Qui T.; Liu, Peter S.; Lill, Jennie R.; Li, Hong; Wu, Jiansheng; Kummerfeld, Sarah (2015-10-29). "Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling". Nature. 526 (7575): 666–671. Bibcode:2015Natur.526..666K. doi:10.1038/nature15541. ISSN 0028-0836. PMID 26375259.
- ^ 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.
- ^ Guo, Haitao; Callaway, Justin B; Ting, Jenny P-Y (July 2015). "Inflammasomes: mechanism of action, role in disease, and therapeutics". Nature Medicine. 21 (7): 677–687. doi:10.1038/nm.3893. ISSN 1078-8956. PMC 4519035. PMID 26121197.