IntroductionThe central function of IL-1β in fever regulation was recognized with its discovery >30 years ago (1Dinarello C.A. Annu. Rev. Immunol. 2009; 27: 519-550Crossref PubMed Scopus (2429) Google Scholar). It was an attractive candidate as a master regulator in the pathogenesis of the hereditary fever syndromes; however, definitive proof was elusive. The mechanisms enabling maturation and release of active IL-1β are complex, and it was difficult to detect the cytokine in patient serum. Validation of its central role in these rare autoinflammatory conditions was achieved in the last decade with the convergence of three major developments in translational medicine research: 1) advances in the techniques used to identify human disease-causing genes, 2) innovations in genomic analysis, and 3) progress in effective targeted biologic therapeutics. Recent years have seen the explosion of exciting research elucidating the principal role of IL-1β in fever disorders and expanding the autoinflammatory disease family beyond rare Mendelian syndromes to include common conditions such as gout and occupational lung disease (2Masters S.L. Simon A. Aksentijevich I. Kastner D.L. Annu. Rev. Immunol. 2009; 27: 621-668Crossref PubMed Scopus (833) Google Scholar). Concurrently, there have been significant advances in understanding the complexity of the innate immune system; the mechanisms regulating IL-1β release; and the host response to pathogens, internal danger signals, and nonpathogenic inflammatory stimuli. With the advent of IL-1-targeted therapy, unprovoked inflammation due to excess IL-1β can be managed and sequelae prevented. New research will continue to unravel the innate immune system's arsenal of sensory proteins and fully reveal the many pathways comprising IL-1β function.Genetics of Inherited Recurrent FeversThe hereditary fever syndromes are a family of inflammatory diseases characterized by recurrent episodes of fever, joint symptoms, and rash. The clear Mendelian inheritance of these conditions combined with improved genetic mapping methods allowed the identification of the underlying genes, beginning with the MEFV gene for familial Mediterranean fever (FMF) 2The abbreviations used are: FMFfamilial Mediterranean feverFCASfamilial cold autoinflammatory syndromeMWSMuckle-Wells syndromeNOMIDneonatal onset multisystem inflammatory diseaseCAPScryopyrin-associated periodic syndromesNBDnucleotide-binding domainLRRleucine-rich repeatTLRToll-like receptorCARDcaspase activation and recruitment domainPYDpyrin domainROSreactive oxygen species. in 1997 following an international effort (3Bernot A. Clepet C. Dasilva C. Devaud C. Petit J.L. Caloustian C. Cruaud C. Samson D. Pulcini F. Weissenbach J. Heilig R. Notanicola C. Domingo C. Rozenbaum M. Benchetrit E. Topaloglu R. Dewalle M. Dross C. Hadjari P. Dupont M. Demaille J. Touitou I. Smaoui N. Nedelec B. Méry J.P. Chaabouni H. Delpech M. Grateau G. Nat. Genet. 1997; 17: 25-31Crossref PubMed Scopus (1262) Google Scholar, 4International FMF Consortium Cell. 1997; 90: 797-807Abstract Full Text Full Text PDF PubMed Scopus (1318) Google Scholar). In the next 2 years, heterozygous mutations in TNFRSF1a, encoding the TNF receptor, were linked to the autosomal dominant disease previously known as familial Hibernian fever, now called the TNF receptor-associated periodic syndrome (5McDermott M.F. Aksentijevich I. Galon J. McDermott E.M. Ogunkolade B.W. Centola M. Mansfield E. Gadina M. Karenko L. Pettersson T. McCarthy J. Frucht D.M. Aringer M. Torosyan Y. Teppo A.M. Wilson M. Karaarslan H.M. Wan Y. Todd I. Wood G. Schlimgen R. Kumarajeewa T.R. Cooper S.M. Vella J.P. Amos C.I. Mulley J. Quane K.A. Molloy M.G. Ranki A. Powell R.J. Hitman G.A. O'Shea J.J. Kastner D.L. Cell. 1999; 97: 133-144Abstract Full Text Full Text PDF PubMed Scopus (1091) Google Scholar). Homozygous mutations in the gene for mevalonate kinase were shown to cause hyperimmunoglobulinemia D with periodic fever syndrome (6Drenth J.P. Cuisset L. Grateau G. Vasseur C. van de Velde-Visser S.D. de Jong J.G. Beckmann J.S. van der Meer J.W. Delpech M. Nat. Genet. 1999; 22: 178-181Crossref PubMed Scopus (475) Google Scholar, 7Houten S.M. Kuis W. Duran M. de Koning T.J. van Royen-Kerkhof A. Romeijn G.J. Frenkel J. Dorland L. de Barse M.M. Huijbers W.A. Rijkers G.T. Waterham H.R. Wanders R.J. Poll-The B.T. Nat. Genet. 1999; 22: 175-177Crossref PubMed Scopus (422) Google Scholar). Although these conditions are clinically related, a unifying underlying mechanism did not become clear until researchers mapped the genetic basis for two unusual fever syndromes, familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), in 2001 (8Hoffman H.M. Mueller J.L. Broide D.H. Wanderer A.A. Kolodner R.D. Nat. Genet. 2001; 29: 301-305Crossref PubMed Scopus (1268) Google Scholar).FCAS and MWS are autosomal dominant conditions; however, further similarities between the two were not immediately recognized, and initially, they were not classified as fever disorders. FCAS is characterized by day-long attacks of rash and joint pain precipitated by exposure to cold temperatures, which, although debilitating, do not generally lead to long-term morbidity (9Hoffman H.M. Wanderer A.A. Broide D.H. J. Allergy Clin. Immunol. 2001; 108: 615-620Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). MWS consists of febrile episodes without the association with cold. In addition, MWS patients develop progressive hearing loss and end-stage renal disease due to amyloidosis (10Shinkai K. McCalmont T.H. Leslie K.S. Clin. Exp. Dermatol. 2008; 33: 1-9PubMed Google Scholar). Patients with both syndromes exhibit a distinctive urticaria-like rash associated with fever, suggesting these two seemingly disparate conditions have a common root. Genetic linkage of both FCAS and MWS to chromosome 1q44 indeed indicated that these diseases are genetically related, and the final identification of heterozygous mutations in the NLRP3 (CIAS1) gene in patients with both disorders was definitive proof (8Hoffman H.M. Mueller J.L. Broide D.H. Wanderer A.A. Kolodner R.D. Nat. Genet. 2001; 29: 301-305Crossref PubMed Scopus (1268) Google Scholar, 11Hoffman H.M. Wright F.A. Broide D.H. Wanderer A.A. Kolodner R.D. Am. J. Hum. Genet. 2000; 66: 1693-1698Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). As more patients were identified with phenotypes falling between FCAS and MWS, it became clear that these syndromes are part of a single disease continuum that was further enlarged by the genetic mapping of a third disorder known as neonatal onset multisystem inflammatory disease (NOMID). In addition to almost daily fevers and an urticaria-like rash, patients with NOMID exhibit a characteristic arthropathy and significant central nervous system involvement (12Aksentijevich I. Nowak M. Mallah M. Chae J.J. Watford W.T. Hofmann S.R. Stein L. Russo R. Goldsmith D. Dent P. Rosenberg H.F. Austin F. Remmers E.F. Balow Jr., J.E. Rosenzweig S. Komarow H. Shoham N.G. Wood G. Jones J. Mangra N. Carrero H. Adams B.S. Moore T.L. Schikler K. Hoffman H. Lovell D.J. Lipnick R. Barron K. O'Shea J.J. Kastner D.L. Goldbach-Mansky R. Arthritis Rheum. 2002; 46: 3340-3348Crossref PubMed Scopus (587) Google Scholar, 13Feldmann J. Prieur A.M. Quartier P. Berquin P. Certain S. Cortis E. Teillac-Hamel D. Fischer A. de Saint Basile G. Am. J. Hum. Genet. 2002; 71: 198-203Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar). To reflect the cold-induced febrile episodes characteristic of FCAS, the NLRP3 gene product was called cryopyrin ("ice fire"; also called NALP3 and NLRP3), and these diseases are collectively known as the cryopyrin-associated periodic syndromes (CAPS).Genomics of InflammationThe Human Genome Project provided an avalanche of raw genomic DNA and cDNA sequences that could be rapidly classified based on homology to proteins of known function. Recognition of conserved domains suggested a commonality of function among wide groups of seemingly distantly related proteins. Researchers studying inflammation and apoptosis mined databases using APAF-1, a scaffold protein that nucleates a caspase-activating complex called the apoptosome, and CIITA, the MHC Class II transactivator (14Li P. Nijhawan D. Budihardjo I. Srinivasula S.M. Ahmad M. Alnemri E.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6182) Google Scholar, 15Steimle V. Otten L.A. Zufferey M. Mach B. Cell. 1993; 75: 135-146Abstract Full Text PDF PubMed Scopus (758) Google Scholar). Dozens of novel intracellular protein candidates were identified, and this family became collectively known as NLR, for nucleotide-binding domain (NBD) and leucine-rich repeats (LRRs). NLR proteins have a central NBD (also known as NOD for nucleotide oligomerization domain) and, like the cell-surface Toll-like receptors (TLRs), contain variable numbers of C-terminal LRR motifs. To reflect their close analogy to TLRs, members of the NLR family are also referred to as NOD-like receptors (Fig. 1) (16Martinon F. Mayor A. Tschopp J. Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1836) Google Scholar).The NLR family is further divided based on the variable N-terminal domain. NLRC proteins are an NLR subset with N-terminal caspase activation and recruitment domains (CARDs), whereas NLRP proteins, including the CAPS protein (cryopyrin/NLRP3), contain a novel death domain family motif known as the pyrin domain (PYD). The PYD was first identified in the protein pyrin, mutated in FMF, a provocative molecular connection between FMF and CAPS (3Bernot A. Clepet C. Dasilva C. Devaud C. Petit J.L. Caloustian C. Cruaud C. Samson D. Pulcini F. Weissenbach J. Heilig R. Notanicola C. Domingo C. Rozenbaum M. Benchetrit E. Topaloglu R. Dewalle M. Dross C. Hadjari P. Dupont M. Demaille J. Touitou I. Smaoui N. Nedelec B. Méry J.P. Chaabouni H. Delpech M. Grateau G. Nat. Genet. 1997; 17: 25-31Crossref PubMed Scopus (1262) Google Scholar, 4International FMF Consortium Cell. 1997; 90: 797-807Abstract Full Text Full Text PDF PubMed Scopus (1318) Google Scholar). Two NLR proteins are known to contain both a PYD and a CARD, including a small adaptor protein known as PYCARD (ASC) and NLRP1, the first NLR protein demonstrated to form a multiprotein complex called the inflammasome (17Martinon F. Burns K. Tschopp J. Mol. Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (4044) Google Scholar).NLR Inflammasomes: Structure and FunctionThe primary function of CARDs is the activation of caspases, but in addition, CARDs, as well as PYDs, NBDs, and LRRs, serve as protein-protein interaction domains in a scaffold for a complex similar to the apoptosome. However, instead of activating caspases mainly involved in apoptosis (such as caspase-3, -8, and -9), NLR-related inflammasome complexes activate caspase-1, also known as the IL-1-converting enzyme. These inflammasomes consist of NLR proteins (NLRP3, NLRP1, and NLRC4), adaptor proteins (PYCARD and possibly CARDINAL), chaperone proteins (heat shock protein 90 and SGT1), and caspases (1 and/or 5) (17Martinon F. Burns K. Tschopp J. Mol. Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (4044) Google Scholar, 18Agostini L. Martinon F. Burns K. McDermott M.F. Hawkins P.N. Tschopp J. Immunity. 2004; 20: 319-325Abstract Full Text Full Text PDF PubMed Scopus (1349) Google Scholar, 19Mariathasan S. Newton K. Monack D.M. Vucic D. French D.M. Lee W.P. Roose-Girma M. Erickson S. Dixit V.M. Nature. 2004; 430: 213-218Crossref PubMed Scopus (1383) Google Scholar). NLR proteins are predicted to form a hexameric or heptameric scaffold allowing adaptors or chaperones to interact based on inter- and intraprotein domain-domain interactions (20Aksentijevich I. Putnam C.D. Remmers E.F. Mueller J.L. Le J. Kolodner R.D. Moak Z. Chuang M. Austin F. Goldbach-Mansky R. Hoffman H.M. Kastner D.L. Arthritis Rheum. 2007; 56: 1273-1285Crossref PubMed Scopus (305) Google Scholar). Multiple molecules of caspase-1 are recruited and concentrated, resulting in proximity-induced cleavage and activation. Mature caspase-1 then cleaves pro-IL-1β and pro-IL-18. Active IL-1β and IL-18 are secreted and initiate multiple inflammatory processes. The inflammasome therefore serves a crucial regulatory role by controlling the release of potent mediators (Fig. 2).FIGURE 2Inflammasome structure and downstream events. Shown is the unfolding of NLRP3 upon sensing various activators, followed by formation of a hexameric complex of NLRP3, CARDINAL, PYCARD, caspase-1, HSP90, and SGT1 proteins. Pro-IL-1β and pro-IL-18 are cleaved, and the active cytokines exit the cell to bind to their respective receptors. IL-18r, IL-18 receptor.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The NLR proteins are thought to function as innate immune sensors of intracellular pathogens that escape the extracellular or membrane-associated TLR armament. Inflammasomes have been implicated in the host response to various Gram-negative and Gram-positive bacteria, including pore-forming and toxin-producing organisms such as Bacillus anthracis (21Terra J.K. Cote C.K. France B. Jenkins A.L. Bozue J.A. Welkos S.L. LeVine S.M. Bradley K.A. J. Immunol. 2010; 184: 17-20Crossref PubMed Scopus (115) Google Scholar), Listeria monocytogenes (22Kim S. Bauernfeind F. Ablasser A. Hartmann G. Fitzgerald K.A. Latz E. 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Hoffman et al. (2011) studied this question.