NLRs at the intersection of cell death and immunity
Abstract
Inflammation is a crucial element of the host response to cellular insult. Pathogen-induced inflammation includes a molecular pathway which proceeds through activation of the protease caspase-1 to the release of the inflammatory cytokines interleukin-1 (IL-1) and IL-18. Importantly, pathogens may also induce forms of cell death that have inherently pro-inflammatory features. Here, we review recent evidence demonstrating that NLR (nucleotide-binding domain, leucine-rich repeat containing) family proteins serve as a common component of both caspase-1-activated apoptotic pathways and caspase-independent necrotic pathways. Parallels are drawn between NLR protein function and the activity of structurally similar proteins involved in cell death: the apoptotic mediator APAF1 (apoptotic-protease-activating factor 1) and the plant disease resistance NBS-LRR (nucleotide-binding site leucine-rich repeats) proteins.
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Polynucleotides and oligonucleotides from degrading DNA or RNA can act on TLR3, TLR7, TLR8, or TLR9 and on intracellular receptors RIG1, MDA5, or LGP2, while ATP and its degradation products may activate or inhibit distinct classes of purinergic receptors.
“Polynucleotides and oligonucleotides derived from degrading DNA or RNA can act on TLR3, TLR7, TLR8, or TLR9 as well as on intracellular receptors including RIG1, MDA5, or LGP2, while ATP and its degradation products may activate or inhibit distinct classes of purinergic receptors 45,108,109.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [108]
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Legionella pneumophila induces apoptosis via the mitochondrial death pathway
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Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009
Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., El-Deiry, W. S., Golstein, P., Green, D. R., et al. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2008.150 · Cited by 3,399 · see citing works
“It remains to be determined whether RIP1 is implicated in pyronecrosis, as well as whether pyroptosis and pyronecrosis play any role outside of the innate immune system.(84,85)”
Caspase Functions in Cell Death and DiseasePreprint
McIlwain, D. R., Berger, T., & Mak, T. W. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008656 · Cited by 2,607 · see citing works
“Activated caspase-1 in turn cleaves pro-IL-1b and pro-IL-18, which facilitates the secretion of these proinflammatory cytokines (Ting et al. 2008b).”
BackgroundInfluentialFatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling
Wen, H., Gris, D., Lei, Y. L., Jha, S., Zhang, L., Huang, M. T.-H., Brickey, W. J., & Ting, J. P. ‐. (2011) · Nature Immunology · doi:10.1038/ni.2022 · Cited by 1,811 · see citing works
“Several NLR molecules including NLRP3, along with the adaptor protein ASC (apoptotic speck protein containing a caspase recruitment domain; also called PYCARD) and procaspase-1, form molecular platforms called the inflammasome, which mediates the catalytic activation of caspase-1, followed by the cleavage and release…”
Self-citationImmunogenic and tolerogenic cell death
Green, D. R., Ferguson, T., Zitvogel, L., & Kroemer, G. (2009) · Nature Reviews Immunology · doi:10.1038/nri2545 · Cited by 1,176 · see citing works
How do plants achieve immunity? Defence without specialized immune cells
Spoel, S. H., & Dong, X. (2012) · Nature reviews. Immunology · doi:10.1038/nri3141 · Cited by 1,114 · see citing works
“However, unlike NLRs in animals, which are known to trigger cell apoptosis through the activity of caspases that activate pro-inflammatory cytokine”
BackgroundAn Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist
Aksentijevich, I. A., Masters, S. L., Ferguson, P. J., Dancey, P., Frenkel, J., van Royen‐Kerkhof, A., Laxer, R. M., Tedgård, U., Cowen, E. W., Pham, T., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0807865 · Cited by 981 · see citing works
Inflammation and Lipid Signaling in the Etiology of Insulin Resistance
Glass, C. K., & Olefsky, J. M. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.001 · Cited by 942 · see citing works
“NLRP3 forms a complex with the adaptor protein ASC (apoptotic speck protein containing a caspase recruitment domain) that regulates caspase 3-dependent cleavage of pro-IL-1b to release active IL-1b (Ting et al., 2008).”
Zinc in Infection and Inflammation
Gammoh, N. Z., & Rink, L. (2017) · Nutrients · doi:10.3390/nu9060624 · Cited by 829 · see citing works
“pro-IL-1β and pro-IL-18, which facilitates the secretion of these proinflammatory cytokines [59].”
BackgroundThe inflammasome: an integrated view
Gross, O., Thomas, C. J., Guarda, G., & Tschopp, J. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01046.x · Cited by 778 · see citing works
“The structural similarities between the apoptosome and the inflammasome came to attention very early in inflammasome research (6) (Fig.”
BackgroundThe signal pathways and treatment of cytokine storm in COVID-19
Yang, L., Xie, X., Tu, Z., Fu, J., Xu, D., & Zhou, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00679-0 · Cited by 599 · see citing works
“IL-1β is perhaps the most well-studied member of the IL-1 family because of its prominent role in autoinflammatory diseases such as gout and chronic inflammatory arthritis.149–151 IL-1β is mainly secreted by macrophages via apoptosis and pyroptosis and exerts positive effects on the migration of immune cells to inflam…”
BackgroundTalkowski, M. E., Rosenfeld, J. A., Blumenthal, I., Pillalamarri, V., Chiang, C., Heilbut, A., Ernst, C., Hanscom, C., Rossin, E., Lindgren, A. M., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.028 · Cited by 577 · see citing works
Pathogen recognition in the innate immune response
Kumar, H., Kawai, T., & Akira, S. (2009) · Biochemical Journal · doi:10.1042/bj20090272 · Cited by 586 · see citing works
Biological and Nutritional Properties of Palm Oil and Palmitic Acid: Effects on Health
Mancini, A., Imperlini, E., Nigro, E., Montagnese, C., Daniele, A., Orrù, S., & Buono, P. (2015) · Molecules · doi:10.3390/molecules200917339 · Cited by 558 · see citing works
“ROS regulate the activation of mature interleukin-1β (IL-1β) from its inactive precursor pro-IL-1β [30,31].”
BackgroundIn Posidonia oceanica cadmium induces changes in DNA methylation and chromatin patterning
Greco, M., Chiappetta, A. A. C., Bruno, L., & Bitonti, M. B. (2011) · Journal of Experimental Botany · doi:10.1093/jxb/err313 · Cited by 533 · see citing works
The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes
Silverman, W. R., Vaccari, J. P. D. R., Locovei, S., Qiu, F., Carlsson, S. K., Scemes, E., Keane, R. W., & Dahl, G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.004804 · Cited by 534 · see citing works
IAP-targeted therapies for cancer
LaCasse, E. C., Mahoney, D. J., Cheung, H. H., Plenchette, S., Baird, S. D., & Korneluk, R. G. (2008) · Oncogene · doi:10.1038/onc.2008.302 · Cited by 524 · see citing works
“NAIP is unique among the IAPs in that it possesses a nucleotide-binding and oligomerization domain as well as leucine-rich repeats that classify this IAP along with other proteins involved in innate immunity, called the nucleotide-binding and oligomerization domain-like receptors (Kanneganti et al., 2007; Mariathasan…”
BackgroundInflammasomes in liver diseases
Szabó, G., & Csák, T. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.03.035 · Cited by 498 · see citing works
“Unlike apoptosis, pyroptosis does not depend on apoptotic caspases and it is accompanied by loss of plasma membrane integrity and lack of chromatin condensation [57].”
BackgroundGroß, O., Yazdi, A. S., Thomas, C. J., Masin, M., Heinz, L. X., Guarda, G., Quadroni, M., Drexler, S. K., & Tschopp, J. (2012) · Immunity · doi:10.1016/j.immuni.2012.01.018 · Cited by 460 · see citing works
The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?
Savio, L. E. B., de Andrade Mello, P., da Silva, C. G., & Coutinho-Silva, R. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00052 · Cited by 437 · see citing works
“The later, in turn, processes pro-IL-1β to its mature form which is able to be released then (Ferrari et al., 1997, 2006; Qu et al., 2007; Ting et al., 2008; Di Virgilio et al., 2017).”
BackgroundNLR family member NLRC5 is a transcriptional regulator of MHC class I genes
Meissner, T. B., Li, A., Biswas, A., Lee, K.-H., Liu, Y.-J., Bayir, E., Iliopoulos, D., van den Elsen, P. J., & Kobayashi, K. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008684107 · Cited by 408 · see citing works
“There are 22 NLR proteins in humans, which share three characteristic functional domains: an N-terminal protein–protein interaction domain such as a caspase recruitment domain (CARD) or a PYRIN domain, a centrally located NBD (or NACHT, NAIP, CIITA, HET-E and TP1 domain), and C-terminal LRRs (11, 12).”
BackgroundInfluentialImmunomodulatory mechanisms of lactobacilli
Wells, J. M. (2011) · Microbial Cell Factories · doi:10.1186/1475-2859-10-s1-s17 · Cited by 431 · see citing works
“There are more than 20 members of this receptor family in humans and they recognize a wide range of bacterial ligands and toxins as well as certain damageassociated molecular patterns (DAMPs) of the host cell [19,54].”
BackgroundUric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis
Gasse, P., Riteau, N., Charron, S., Girre, S., Fick, L., Pétrilli, V., Tschopp, J., Lagente, V., Quesniaux, V. F. J., Ryffel, B., et al. (2009) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200808-1274oc · Cited by 410 · see citing works
Sugars and plant innate immunity
Moghaddam, M. R. B., & den Ende, W. V. (2012) · Journal of Experimental Botany · doi:10.1093/jxb/ers129 · Cited by 386 · see citing works
“Recently, HSP90 and HSC70, important players in plant (Ting et al., 2008) and animal (Shirasu, 2009) innate immunity, have been reported to fulfil a critical role in stomatal closure and modulation of physiological responses to ABA (Clément et al.”
BackgroundIntracellular staphylococcus aureus: Live-in and let die
Fraunholz, M. J., & Sinha, B. N. M. (2012) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2012.00043 · Cited by 380 · see citing works
Bonardi, V., Tang, S., Stallmann, A., Roberts, M., Cherkis, K., & Dangl, J. L. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113726108 · Cited by 365 · see citing works
“atrbohD (2), lsd1-2 (3), npr1-1 (4), rps2-101C (5), rpm1-3 (6), sid2-1 (7), fls2 (8), and efr (8) are described elsewhere.”
BackgroundMechanism of action of clinically approved adjuvants
Lambrecht, B. N., Kool, M., Willart, M. A. M., & Hammad, H. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.01.004 · Cited by 354 · see citing works
NB-LRR proteins: pairs, pieces, perception, partners, and pathways
Eitas, T. K., & Dangl, J. L. (2010) · Current Opinion in Plant Biology · doi:10.1016/j.pbi.2010.04.007 · Cited by 353 · see citing works
“com NLR proteins, initiate cell death, inflammation, and responses to pathogens in mammalian cells [2].”
Molecular mechanisms involved in inflammasome activation
Bryant, C. E., & Fitzgerald, K. A. (2009) · Trends in Cell Biology · doi:10.1016/j.tcb.2009.06.002 · Cited by 351 · see citing works
Neutrophil Recruitment to the Lungs during Bacterial Pneumonia
Craig, A., Mai, J., Cai, S., & Jeyaseelan, S. (2008) · Infection and Immunity · doi:10.1128/iai.00832-08 · Cited by 349 · see citing works
“Recent studies have demonstrated that NOD-dependent signaling cascades can also activate NF- B (76, 84).”
BackgroundInfluentialWillingham, S. B., Allen, I. C., Bergstralh, D. T., Brickey, W. J., Huang, M. T.-H., Taxman, D. J., Duncan, J. A., & Ting, J. P. ‐. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900138 · Cited by 348 · see citing works
“Although pyronecrosis requires cathepsin B but not caspase activity, pyroptosis requires the activity of caspase-1 (21).”
BackgroundSelf-citationInflammasomes: too big to miss
Stutz, A., Golenbock, D. T., & Latz, E. (2009) · Journal of Clinical Investigation · doi:10.1172/jci40599 · Cited by 345 · see citing works
Liu, J., Elmore, J. M., Lin, Z.-J. D., & Coaker, G. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.01.010 · Cited by 334 · see citing works
“Plant NB-LRR immune receptors are structurally analogous to animal NLR (nucleotide-binding domain, leucine-rich repeat containing) receptors (Ting et al., 2008).”
BackgroundAbulafia, D. P., de Rivero Vaccari, J. P., Lozano, J. D., Lotocki, G., Keane, R. W., & Dietrich, W. D. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.143 · Cited by 322 · see citing works
“…including the nucleotide-binding, leucine-rich repeat, pyrin domain containing 1 (NLRP1), the NLRP3 and the nucleotide-binding, leucine-rich repeat, CARD domain containing 4 (NLRC4) inflammasome (Tschopp et al, 2003; Agostini et al, 2004; Dinarello, 2005; Miao et al, 2006; Ting et al, 2008).”
BackgroundSingh, R. P., Singh, K. P., Cherian, S., Saminathan, M., Kapoor, S., Reddy, G. B. M., Panda, S., & Dhama, K. (2017) · Veterinary Quarterly · doi:10.1080/01652176.2017.1343516 · Cited by 320 · see citing works
“of caspase 1, when compared to apoptosis and thereby results in necrosis (Ting et al. 2008).”
BackgroundThe role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis
Lavelle, E. C., Murphy, C. H., O'Neill, L. A. J., & Creagh, E. M. (2009) · Mucosal Immunology · doi:10.1038/mi.2009.124 · Cited by 291 · see citing works
Caspase-1: The inflammasome and beyond
Sollberger, G., Strittmatter, G. E., Garstkiewicz, M., Sand, J., & Beer, H. (2013) · Innate Immunity · doi:10.1177/1753425913484374 · Cited by 275 · see citing works
Monocytic microparticles activate endothelial cells in an IL-1β–dependent manner
Wang, J.-G., Williams, J., Davis, B. K., Jacobson, K., Doerschuk, C. M., Ting, J. P. ‐., & Mackman, N. (2011) · Blood · doi:10.1182/blood-2011-01-330878 · Cited by 259 · see citing works
Self-citationInnate Immune Responses to Danger Signals in Systemic Inflammatory Response Syndrome and Sepsis
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“Cells of the immune system rely on specific receptors to detect the presence of exogenous and endogenous danger signals (lipopolysacharide [LPS], bacterial toxins, viral proteins) that subsequently trigger an immediate innate proinflammatory response.(31,32) Several trans-membrane proteins are identified as pattern re…”
Interaction of staphylococci with bone
Wright, J. A., & Nair, S. P. (2009) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2009.10.003 · Cited by 258 · see citing works
“This complex consists of caspase-1, the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) and one of several NLR proteins, of which four are known to associate with inflammasomes (Ting et al., 2008).”
BackgroundAn Inflammasome-Independent Role for Epithelial-Expressed Nlrp3 in Renal Ischemia-Reperfusion Injury
Shigeoka, A. A., Mueller, J. L., Kambo, A., Mathison, J. C., King, A. J., Hall, W. F., Correia, J. D. S., Ulevitch, R. J., Hoffman, H. M., & McKay, D. B. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002330 · Cited by 229 · see citing works
Mechanisms of uric acid crystal‐mediated autoinflammation
Martinon, F. (2009) · Immunological Reviews · doi:10.1111/j.0105-2896.2009.00860.x · Cited by 223 · see citing works
“Although IPAF ⁄ NLRC4, NALP3 ⁄ NLRP3, and NALP1 ⁄NLRP1 inflammasomes define the general structure of NLR inflammasome complexes, recent observations suggest that other NLRs, such as NAIP or NOD2, may be involved in forming NLR inflammasomes or in modulating their activity (49, 59).”
BackgroundRIG-I-like receptors: Sensing and responding to RNA virus infection
Nakhaei, P., Génin, P., Civas, A., & Hiscott, J. B. (2009) · Seminars in Immunology · doi:10.1016/j.smim.2009.05.001 · Cited by 222 · see citing works
Critical role for NLRP3 in necrotic death triggered by <i>Mycobacterium tuberculosis</i>
Wong, K., & Jacobs Jr, W. R. (2011) · Cellular Microbiology · doi:10.1111/j.1462-5822.2011.01625.x · Cited by 209 · see citing works
“The second type, called pyronecrosis, is caspase-1independent (Ting et al., 2008).”
BackgroundInfluentialCathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways
Xie, Z., Zhao, M., Yan, C., Kong, W., Lan, F., Narengaowa, Zhao, S., Yang, Q., Bai, Z., Qing, H., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05786-0 · Cited by 217 · see citing works
“between pyronecrosis and pyroptosis, such as their differential dependence on caspase-1, they are evidently both pathways which respond to pathogens by promoting the inherently proinflammatory release of cellular contents [26].”
BackgroundNLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer
Karki, R., Man, S. M., Malireddi, R. K. S., Kesavardhana, S., Zhu, Q., Burton, A. R., Sharma, B. R., Qi, X., Pelletier, S. W., Vogel, P., et al. (2016) · Nature · doi:10.1038/nature20597 · Cited by 215 · see citing works
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“Effector-triggered immunity (ETI) is activated by the recognition of pathogen-derived effector proteins by intracellular NB-LRR proteins that share structural features with animal nucleotide-binding domain, leucine-rich repeat containing (NLR) proteins (3).”
BackgroundScaffold proteins and immune-cell signalling
Shaw, A. S., & Filbert, E. L. (2008) · Nature reviews. Immunology · doi:10.1038/nri2473 · Cited by 211 · see citing works
“A second large and highly conserved family of innate immune receptors is the nucleotide-binding domain and leucine-rich-repeat-containing (NLR) famil”
BackgroundCutting Edge: NLRC5-Dependent Activation of the Inflammasome
Davis, B. K., Roberts, R. A., Huang, M. T.-H., Willingham, S. B., Conti, B. J., Brickey, W. J., Barker, B. R., Kwan, M., Taxman, D. J., Accavitti-Loper, M. A., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1003111 · Cited by 208 · see citing works
“Pathogen-mediated activation of caspase 1 and/or NLRs can induce several cell death pathways that are broadly characterized as proinflammatory because they result in the further release of inflammatory molecules (13, 14).”
BackgroundSelf-citationHitomi, Y., Ebisawa, M., Tomikawa, M., Imai, T., Komata, T., Hirota, T., Harada, M., Sakashita, M., Suzuki, Y., Shimojo, N., et al. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.07.044 · Cited by 206 · see citing works
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“Members of the NLR family assemble into large multiprotein complexes ( 700 kDa), termed inflammasomes, that can be activated by cellular pathogens (bacteria, fungi, viruses, and protozoa) or stress to engage innate immune defenses (23, 35).”
BackgroundGao, Z., Chung, E., Eitas, T. K., & Dangl, J. L. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104410108 · Cited by 197 · see citing works
“Plant NB-LRR proteins are structurally and functionally analogous to animal nucleotide-binding leucine-rich repeat receptor (NLR) innate immune receptors (3, 4).”
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Caspase-7 Activation by the Nlrc4/Ipaf Inflammasome Restricts Legionella pneumophila Infection
Akhter, A., Gavrilin, M. A., Frantz, L. J., Washington, S., Ditty, C., Limoli, D. H., Day, C., Sarkar, A., Newland, C. A., Butchar, J. P., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000361 · Cited by 191 · see citing works
“These cytosolic receptors belong to the nucleotide binding oligomerization domain-leucine rich repeat proteins (NOD-likereceptors or CATERPILLAR family of proteins) [7–12].”
BackgroundConcepts in the Pathogenesis of Rabies
Dietzschold, B., Li, J., Faber, M., & Schnell, M. J. (2008) · Future Virology · doi:10.2217/17460794.3.5.481 · Cited by 193 · see citing works
“Alternatively, RV infection and, in particular, the overexpression of the RV G protein might result in pyroptosis, a cell death pathway similar to apoptosis, which, in contrast to apoptosis, involves the activation of caspase 1 and thereby leading to necrosis [61].”
BackgroundAmelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction
Chen, G., Chen, X., King, S., Cavassani, K. A., Cheng, J., Zheng, X., Cao, H., Yu, H., Qu, J., Fang, D., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1846 · Cited by 190 · see citing works
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“transduction elements involved in the hypersensitive response (a pathway leading to PCD; Innes and DeYoung, 2006; Ting et al., 2008).”
BackgroundPure Hemozoin Is Inflammatory In Vivo and Activates the NALP3 Inflammasome via Release of Uric Acid
Griffith, J. W., Sun, T., McIntosh, M. T., & Bucala, R. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0713552 · Cited by 187 · see citing works
“Two of the best studied NLR family members are IPAF and NALP3, and these have been shown to be indispensable for the production of IL-1 in response to a large number of pathogens and endogenous molecules (41).”
BackgroundInflammasome signaling at the heart of central nervous system pathology
Chakraborty, S., Kaushik, D. K., Gupta, M., & Basu, A. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22343 · Cited by 186 · see citing works
“APAF-1 bears close structural resemblance to NLRs with a CARD domain for recruiting caspase-9, which corroborates the idea that low intracellular K(1)activated apoptosomes evoke exclusively apoptotic cell death, while activated inflammasomes mediate inflammation along with pyroptotic cell-death (Ting et al., 2008).”
BackgroundMeixenberger, K., Pache, F. C., Eitel, J., Schmeck, B., Hippenstiel, S., Slevogt, H., N’Guessan, P. D., Witzenrath, M., Netea, M. G., Chakraborty, T., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901346 · Cited by 186 · see citing works
Santoni, G., Cardinali, C., Morelli, M. B., Santoni, M., Nabissi, M., & Amantini, C. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0239-2 · Cited by 176 · see citing works
“Inflammasome proteins and even the functional machinery of inflammasomes have been linked to cell death in several cell types [123].”
BackgroundHolzinger, D., Gieldon, L., Mysore, V., Nippe, N., Taxman, D. J., Duncan, J. A., Broglie, P. M., Marketon, K., Austermann, J., Vogl, T., et al. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0112014 · Cited by 170 · see citing works
“Nevertheless, CTSB inhibition only partially reduced cell death, and therefore, programmed necrosis, socalled pyronecrosis [65], is not the only pathway leading to PVLmediated necrosis.”
BackgroundThe P2X7 receptor–pannexin connection to dye uptake and IL-1β release
Pelegrı́n, P., & Surprenant, A. (2009) · Purinergic Signalling · doi:10.1007/s11302-009-9141-7 · Cited by 169 · see citing works
“[72] Purinergic Signalling (2009) 5:129–137 133”
The Pathology of Orthopedic Implant Failure Is Mediated by Innate Immune System Cytokines
Landgraeber, S., Jäger, M., Jacobs, J. J., & Hallab, N. J. (2014) · Mediators of Inflammation · doi:10.1155/2014/185150 · Cited by 167 · see citing works
“Effective immune system activation requires specific receptors that recognize both pathogen associated molecular patterns (PAMPs) and danger associatedmolecular patterns (DAMPs) to initiate innate proinflammatory responses, Figures 1 and 3 [61, 62].”
BackgroundMechanisms of Neutrophil Accumulation in the Lungs Against Bacteria
Balamayooran, G., Batra, S., Fessler, M. B., Happel, K. I., & Jeyaseelan, S. (2009) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2009-0047tr · Cited by 165 · see citing works
“NLRs are characterized by the presence of a central NOD domain, a C-terminal LRR, and an N-terminal domain, including CARD or the putative protein–protein interaction (PYRIN) domain (37).”
BackgroundInfluentialAmyloid‐β oligomers set fire to inflammasomes and induce Alzheimer's pathology
Salminen, A., Ojala, J. O., Suuronen, T., Kaarniranta, K., & Kauppinen, A. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00496.x · Cited by 162 · see citing works
“2258 APAF-1 protein is structurally very similar to NOD-like receptors, containing a CARD motif for the recruitment of caspase-9 [34].”
BackgroundInfluentialMcElvania, E., Allen, I. C., Hulseberg, P. D., Sullivan, J. T., McCann, J. R., Sándor, M., Braunstein, M., & Ting, J. P. ‐. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012320 · Cited by 155 · see citing works
“In addition to these inflammatory functions, PYCARD association with NLR proteins is required for pyroptotic and pyronecrotic cell death [19,20].”
BackgroundSelf-citationShaw, P. J., Lukens, J. R., Burns, S., Chi, H., McGargill, M. A., & Kanneganti, T. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000217 · Cited by 160 · see citing works
Morishige, T., Yoshioka, Y., Inakura, H., Tanabe, A., Yao, X., Narimatsu, S., Monobe, Y., Imazawa, T., Tsunoda, S., Tsutsumi, Y. M., et al. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.05.036 · Cited by 153 · see citing works
“Pyronecrosis is considered to elicit substantial inflammation and to affect the local environment, whereas apoptosis is widely accepted as non-inflammatory cell death without effects around the dying cells [48].”
Shigella Induces Mitochondrial Dysfunction and Cell Death in Nonmyleoid Cells
Carneiro, L. A. M., Travassos, L. H., Soares, F., Tattoli, I., Magalhaes, J. G., Bozza, M. T., Plotkowski, M. C., Sansonetti, P. J., Molkentin, J. D., Philpott, D. J., et al. (2009) · Cell Host & Microbe · doi:10.1016/j.chom.2008.12.011 · Cited by 155 · see citing works
“In macrophages, the NLR family members NLRC4 and NLRP3 mediate Shigella-induced pyroptosis and pyronecrosis, respectively, with activation of the caspase-1 inflammasome and subsequent IL-1b processing and release (Ting et al., 2008).”
InfluentialLi, L., Lu, Q., Chen, W., Li, J., Li, C., & Zheng, Z. J. (2018) · Journal of Diabetes Research · doi:10.1155/2018/8193523 · Cited by 154 · see citing works
“The NLRP3 inflammasome induces inflammation by mediating the catalytic activation of caspase-1, followed by the cleavage and release of the proinflammatory cytokines IL-1β and IL-18 [25, 26].”
BackgroundChen, G., Brown, N. K., Wu, W., Khedri, Z., Yu, H., Chen, X., van de Vlekkert, D., d’Azzo, A., Zheng, P., & Liu, Y. (2014) · eLife · doi:10.7554/elife.04066 · Cited by 150 · see citing works
“, 2012) and cellular injuries (Ting et al., 2008; Tschopp and Schroder, 2010).”
BackgroundEvolutionary Convergence and Divergence in NLR Function and Structure
Meunier, É., & Brož, P. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.04.005 · Cited by 152 · see citing works
“the eighth conserved member of this group, but it differs structurally because its NBD is not strictly a NACHT domain and because it contains WD40 repeats instead of LRRs [33,36,37].”
BackgroundThe Role of Inflammasome-Dependent and Inflammasome-Independent NLRP3 in the Kidney
Kim, Y., Kim, S., Kim, K., Lee, S.-H., & Moon, J.-Y. (2019) · Cells · doi:10.3390/cells8111389 · Cited by 151 · see citing works
“AKI caused by IRI is attenuated in NLRP3, ASC, or caspase 1 KO kidneys [11,53].”
BackgroundPyroptosis – a cell death modality of its kind?
Kepp, O., Galluzzi, L., Zitvogel, L., & Kroemer, G. (2010) · European Journal of Immunology · doi:10.1002/eji.200940160 · Cited by 147 · see citing works
Control of infection by pyroptosis and autophagy: role of TLR and NLR
Bortoluci, K. R., & Medzhitov, R. M. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0335-5 · Cited by 148 · see citing works
“However, the idea of pyroptotic cell death as an effector mechanism of the host cell to control infections by itself is a matter of debate [9, 28, 42].”
BackgroundCD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns
Liu, Y., Chen, G.-Y., & Zheng, P. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.09.006 · Cited by 147 · see citing works
Sensors of the innate immune system: their mode of action
Baccalà, R., González‐Quintial, R., Lawson, B. R., Stern, M. E., Kono, D. H., Beutler, B., & Theofilopoulos, A. N. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.136 · Cited by 145 · see citing works
“NLR activation mediates inflammation and immunity not only through the induction of pyrogenic and inflammatory cytokines, but also by promoting cell death”
BackgroundModulation of obesity-induced inflammation by dietary fats: mechanisms and clinical evidence
Teng, K., Chang, C.-Y., Chang, L. F., & Nesaretnam, K. (2014) · Nutrition Journal · doi:10.1186/1475-2891-13-12 · Cited by 144 · see citing works
“This complex regulates the cleavage of interleukin-1β (IL-1β) from pro-IL-1β [40,41].”
BackgroundType-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications
Musella, M., Manic, G., Maria, R. D., Vitale, I., & Sistigu, A. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1314424 · Cited by 138 · see citing works
“nucleotide-binding domain and a C-terminal leucinerich repeat domain.(22) Among the more than 20 NLRs identified in humans so far,(22) only the cytosolic molecular sensor NODcontaining protein 2 (NOD2) was clearly shown to recognize”
BackgroundExpression Regulation of Major Histocompatibility Complex Class I and Class II Encoding Genes
van den Elsen, P. J. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00048 · Cited by 139 · see citing works
“CIITA belongs to the large NLR (nucleotide binding domain, leucine-rich repeat containing) family of proteins that play multiple functions in innate immune responses (Harton et al., 2002; Ting et al., 2008).”
BackgroundInnate instruction of adaptive immunity revisited: the inflammasome
Eisenbarth, S. C., & Flavell, R. A. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900014 · Cited by 130 · see citing works
“Keywords: aluminium hydroxide; caspase-1; inflammasome; nalp3; toll-like receptors DOI 10.1002/emmm.200900014”
BackgroundInfluentialInterleukin-1, inflammasomes, autoinflammation and the skin
Contassot, E., Beer, H.-D., & French, L. E. (2012) · Swiss Medical Weekly · doi:10.4414/smw.2012.13590 · Cited by 130 · see citing works
Welin, A., Eklund, D., Stendahl, O. I., & Lerm, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020302 · Cited by 127 · see citing works
“This is consistent with the morphological features observed [11,12,26], including DNA fragmentation, which is a hallmark of apoptosis, but has also been observed in a disorganized fashion during necrosis [12,48,49].”
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Nod2: A Critical Regulator of Ileal Microbiota and Crohn’s Disease
Sidiq, T., Yoshihama, S., Downs, I., & Kobayashi, K. S. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00367 · Cited by 129 · see citing works
“NLRs have a tripartite structure consisting of an aminoterminal effector domain, a central NBD, and a carboxy-terminal LRR (17).”
BackgroundInfluentialThe Antisocial Network: Cross Talk Between Cell Death Programs in Host Defense
Snyder, A. G., & Oberst, A. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-112019-072301 · Cited by 129 · see citing works
“Strikingly, the activation of APAF-1 by cytochrome c following MOMP—central to the apoptotic pathway—closely mirrors inflammasome activation (106).”
BackgroundSun, X., Hao, H., Han, Q., Song, X., Liu, J., Dong, L., Han, W., & Mu, Y. (2017) · Stem Cell Research & Therapy · doi:10.1186/s13287-017-0668-1 · Cited by 129 · see citing works
“The processing requires two signals: the first can be achieved by LPS stimulation to induce the IL-1β and IL-18 production from pro-IL-1β and pro-IL-18; and saturated fatty acids are the second signal to activate the inflammasome to further cause the release of procaspase-1 to caspase-1.”
InfluentialWang, S., Gu, Y., Zebell, S. G., Anderson, L. K., Wang, W., Mohan, R., & Dong, X. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.10.005 · Cited by 125 · see citing works
“In the mammalian system, activation of NLRs can trigger programmed cell death (PCD) through recruitment of caspases (Ting et al., 2008).”
BackgroundToll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli
Rapsinski, G. J., Wynosky-Dolfi, M. A., Oppong, G. O., Tursi, S. A., Wilson, R. P., Brodsky, I. E., & Tükel, Ç. (2014) · Infection and Immunity · doi:10.1128/iai.02370-14 · Cited by 123 · see citing works
“343 Activation of inflammasomes can lead to the pyroptosis via caspase-1 activation 344 (47, 48).”
BackgroundThe NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders
Benetti, E., Chiazza, F., Patel, N. S. A., & Collino, M. (2013) · Mediators of Inflammation · doi:10.1155/2013/678627 · Cited by 121 · see citing works
“We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.”
BackgroundYuen, B., Bayes, J. M., & Degnan, S. M. (2013) · Molecular Biology and Evolution · doi:10.1093/molbev/mst174 · Cited by 117 · see citing works
“To investigate the origin of the bona fide NLRs (as defined by the NACHT-LRR domain combination; Ting, Harton et al. 2008), a number of fungal, plant, protozoan, and metazoan genomes were also interrogated (supplementary file S2, Supplementary Material online).”
BackgroundInfluentialSweet immunity in the plant circadian regulatory network
Moghaddam, M. R. B., & den Ende, W. V. (2013) · Journal of Experimental Botany · doi:10.1093/jxb/ert046 · Cited by 118 · see citing works
Pannexin1 as mediator of inflammation and cell death
Yanguas, S. C., Willebrords, J., Johnstone, S. R., Maes, M., Decrock, E., Bock, M. D., Leybaert, L., Cogliati, B., & Vinken, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.10.006 · Cited by 119 · see citing works
“This mechanism is caspase 11 independent and mainly implies the contribution of the NLRC4 inflammasome [125].”
BackgroundInfluentialClément, M., Leonhardt, N., Droillard, M., Reiter, I. M., Montillet, J., Genty, B., Laurière, C., Nussaume, L., & Noël, L. D. (2011) · PLANT PHYSIOLOGY · doi:10.1104/pp.111.174425 · Cited by 115 · see citing works
“Molecular chaperones are key components of innate immunity in mammals (Ting et al., 2008) and plants (Shirasu, 2009).”
BackgroundToxicology of Autoimmune Diseases
Pollard, K. M., Hultman, P. A., & Kono, D. H. (2010) · Chemical Research in Toxicology · doi:10.1021/tx9003787 · Cited by 115 · see citing works
Tumor-host interactions: the role of inflammation
Bitoux, M. L., & Stamenkovic, I. (2008) · Histochemistry and Cell Biology · doi:10.1007/s00418-008-0527-3 · Cited by 112 · see citing works
“Depending on the stimulus, caspase-1, also called IL-1 converting enzyme (ICE), can induce secretion of pro-inXammatory cytokines or trigger cell pyroptosis, a caspase-1-dependent cell death pathway (Ting et al. 2008).”
Cell death and autophagy in tuberculosis
Moraco, A. H., & Kornfeld, H. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.10.001 · Cited by 106 · see citing works
The role of mitochondria in cellular defense against microbial infection
Arnoult, D., Carneiro, L. A. M., Tattoli, I., & Girardin, S. E. (2009) · Seminars in Immunology · doi:10.1016/j.smim.2009.05.009 · Cited by 107 · see citing works
mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process
Marafie, S. K., Al‐Mulla, F., & Abubaker, J. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25116141 · Cited by 110 · see citing works
“NLRs are a family of cytoplasmic sensors that regulate a range of biological functions involved in immunity against infectious diseases [54] and are central regulators of intestinal homeostasis [55].”
Background
- Authors
- Ting, J. P.-Y., Willingham, S. B., & Bergstralh, D. T.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Ting, Jenny P.-Y.
- ORCID
- Ting, Jenny P.-Y.
- Venue
- Nature Reviews Immunology
- Published
- 2008-05
- Volume
- 8
- Issue
- 5
- Pages
- 372-379
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- OpenAlex
- W2050870561
- Cited by
- 371
- References
- 145
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 10 · 2019: 19 · 2018: 18 · 2017: 18 · 2016: 17 · 2015: 19 · 2014: 22 · 2013: 27 · 2012: 36
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- NLR proteins, cell death, pyroptosis, caspase-1, apoptosis, necrosis, inflammation, interleukin-1, IL-18, Apaf-1, NBS-LRR proteins, plant disease resistance, host-pathogen interaction
- MeSH terms
- NLR Proteins, Leucine-Rich Repeat Proteins, Animals, Communicable Diseases, Humans, Interleukin-1, Necrosis, Proteins, Tumor Necrosis Factor-alpha, Apoptosis, Caspase 1, HMGB1 Protein, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Apoptotic Protease-Activating Factor 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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