The nucleotide-binding oligomerization domain, leucine-rich repeat (NLR) family of receptors (nomenclature recommended by the NC-IUPHAR subcommittee on pattern recognition receptors [2]) share a common domain organisation. This consists of an N-terminal effector domain, a central nucleotide-binding and oligomerization domain (NOD; also referred to as a NACHT domain), and C-terminal leucine-rich repeats (LRR) which have regulatory and ligand recognition functions. The type of effector domain has resulted in the division of NLR family members into two major sub-families, NLRC and NLRP, along with three smaller sub-families NLRA, NLRB and NLRX [9]. NLRC members express an N-terminal caspase recruitment domain (CARD) and NLRP members an N-terminal Pyrin domain (PYD).

Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase RIPK2 (receptor interacting serine/threonine kinase 2, O43353, also known as CARD3, CARDIAK, RICK, RIP2) leading to signalling through NFκB and MAP kinase. Activation of NLRC4 (previously known as IPAF) and members of the NLRP3 family, including NLRP1 and NLRP3, leads to formation of a large multiprotein complex known as the inflammasome. In addition to NLR proteins other key members of the inflammasome include the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD, also known as PYCARD, CARD5, TMS1, Q9ULZ3) and inflammatory caspases. The inflammasome activates the pro-inflammatory cytokines IL-1β (IL1B, P01584) and IL-18 (IL18, Q14116) [2,4].

NLRP3 has also been reported to respond to host-derived products, known as danger-associated molecular patterns, or DAMPs, including uric acid [6], ATP, L-glucose, hyaluronan and amyloid β (APP, P05067) [8].

Loss-of-function mutations of NLRP3 are associated with cold autoinflammatory and Muckle-Wells syndromes.

This family also includes NLR family, apoptosis inhibitory protein (NAIP, Q13075) which can be found in the 'Inhibitors of apoptosis (IAP) protein family' in the Other protein targets section of the Guide.

* Key recommended reading is highlighted with an asterisk

* Broz P, Dixit VM. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol, 16 (7): 407-20. [PMID:27291964]

* Bryant CE, Orr S, Ferguson B, Symmons MF, Boyle JP, Monie TP. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol Rev, 67 (2): 462-504. [PMID:25829385]

Corridoni D, Chapman T, Ambrose T, Simmons A. (2018) Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease. Front Med (Lausanne), 5: 32. [PMID:29515999]

Heneka MT, McManus RM, Latz E. (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci, 19 (10): 610-621. [PMID:30206330]

* Keestra-Gounder AM, Tsolis RM. (2017) NOD1 and NOD2: Beyond Peptidoglycan Sensing. Trends Immunol, 38 (10): 758-767. [PMID:28823510]

Kong X, Yuan Z, Cheng J. (2017) The function of NOD-like receptors in central nervous system diseases. J Neurosci Res, 95 (8): 1565-1573. [PMID:28029680]

* Lei-Leston AC, Murphy AG, Maloy KJ. (2017) Epithelial Cell Inflammasomes in Intestinal Immunity and Inflammation. Front Immunol, 8: 1168. [PMID:28979266]

* Man SM. (2018) Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. Nat Rev Gastroenterol Hepatol, 15 (12): 721-737. [PMID:30185915]

Motta V, Soares F, Sun T, Philpott DJ. (2015) NOD-like receptors: versatile cytosolic sentinels. Physiol Rev, 95 (1): 149-78. [PMID:25540141]

* Mukherjee T, Hovingh ES, Foerster EG, Abdel-Nour M, Philpott DJ, Girardin SE. (2019) NOD1 and NOD2 in inflammation, immunity and disease. Arch Biochem Biophys, 670: 69-81. [PMID:30578751]

* Nielsen AE, Hantho JD, Mancini RJ. (2017) Synthetic agonists of NOD-like, RIG-I-like, and C-type lectin receptors for probing the inflammatory immune response. Future Med Chem, 9 (12): 1345-1360. [PMID:28776416]

Patin EC, Thompson A, Orr SJ. (2019) Pattern recognition receptors in fungal immunity. Semin Cell Dev Biol, 89: 24-33. [PMID:29522806]

Zhang H, Li F, Li WW, Stary C, Clark JD, Xu S, Xiong X. (2016) The inflammasome as a target for pain therapy. Br J Anaesth, 117 (6): 693-707. [PMID:27956668]

1. Baldwin AG, Rivers-Auty J, Daniels MJD, White CS, Schwalbe CH, Schilling T, Hammadi H, Jaiyong P, Spencer NG, England H et al.. (2017) Boron-Based Inhibitors of the NLRP3 Inflammasome. Cell Chem Biol, 24 (11): 1321-1335.e5. [PMID:28943355]

2. Bryant CE, Orr S, Ferguson B, Symmons MF, Boyle JP, Monie TP. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol Rev, 67 (2): 462-504. [PMID:25829385]

3. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A et al.. (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med, 21 (3): 248-55. [PMID:25686105]

4. Davis BK, Wen H, Ting JP. (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol, 29: 707-35. [PMID:21219188]

5. Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q et al.. (2017) Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med, 214 (11): 3219-3238. [PMID:29021150]

6. 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. [PMID:16407889]

7. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S. (2009) Activation of innate immune antiviral responses by Nod2. Nat Immunol, 10 (10): 1073-80. [PMID:19701189]

8. Schroder K, Tschopp J. (2010) The inflammasomes. Cell, 140 (6): 821-32. [PMID:20303873]

9. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA et al.. (2008) The NLR gene family: a standard nomenclature. Immunity, 28 (3): 285-7. [PMID:18341998]

10. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD et al.. (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med, 21 (3): 263-9. [PMID:25686106]

Clare Bryant Professor of Innate Immunity The Department of Veterinary Medicine The University of Cambridge Madingley Road Cambridge, UK, CB3 0ES UK Tom P. Monie Assistant Director (Academic) and Academic Director for STEM (Biological) Institute of Continuing Education University of Cambridge Madingley Hall Madingley Cambridge CB3 0ES UK