FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2028145763> ?p ?o ?g. }

• W2028145763 endingPage "107" @default.
• W2028145763 startingPage "96" @default.
• W2028145763 abstract "Yersinia pestis, the causative agent of plague, is able to suppress production of inflammatory cytokines IL-18 and IL-1β, which are generated through caspase-1-activating nucleotide-binding domain and leucine-rich repeat (NLR)-containing inflammasomes. Here, we sought to elucidate the role of NLRs and IL-18 during plague. Lack of IL-18 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an attenuated strain producing a Y. pseudotuberculosis-like hexa-acylated lipid A. We found that the NLRP12 inflammasome was an important regulator controlling IL-18 and IL-1β production after Y. pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge. NLRP12 also directed interferon-γ production via induction of IL-18, but had minimal effect on signaling to the transcription factor NF-κB. These studies reveal a role for NLRP12 in host resistance against pathogens. Minimizing NLRP12 inflammasome activation may have been a central factor in evolution of the high virulence of Y. pestis. Yersinia pestis, the causative agent of plague, is able to suppress production of inflammatory cytokines IL-18 and IL-1β, which are generated through caspase-1-activating nucleotide-binding domain and leucine-rich repeat (NLR)-containing inflammasomes. Here, we sought to elucidate the role of NLRs and IL-18 during plague. Lack of IL-18 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an attenuated strain producing a Y. pseudotuberculosis-like hexa-acylated lipid A. We found that the NLRP12 inflammasome was an important regulator controlling IL-18 and IL-1β production after Y. pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge. NLRP12 also directed interferon-γ production via induction of IL-18, but had minimal effect on signaling to the transcription factor NF-κB. These studies reveal a role for NLRP12 in host resistance against pathogens. Minimizing NLRP12 inflammasome activation may have been a central factor in evolution of the high virulence of Y. pestis. NLRP12 is an inflammasome component in the recognition of Yersinia pestis NLRP12 and IL-18 participate in host resistance to Y. pestis and attenuated strains Minimizing inflammasome signaling may have contributed to evolution of high virulence NLRP12 induces IFN-γ via IL-18 signaling Inflammasomes are multimolecular complexes consisting of inactive pro-caspase-1 and members of the nucleotide-binding domain-leucine-rich repeat (NLR) family of immune system proteins (Latz, 2010Latz E. The inflammasomes: mechanisms of activation and function.Curr. Opin. Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar). The assembly of an inflammasome leads to proteolytic activation of caspase-1, which in turn cleaves pro-interleukin (IL)-1β and pro-IL-18 into mature forms (Latz, 2010Latz E. The inflammasomes: mechanisms of activation and function.Curr. Opin. Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar). Active IL-1β and IL-18 are essential members of host defenses toward various pathogens and may also participate in sterile inflammatory processes. The NLR family has more than 20 members; however, many of these proteins have unknown functions (Martinon et al., 2009Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1863) Google Scholar), and their relative roles in promoting resistance to infection are in many instances unclear. There is evidence supporting a function in bacterial recognition for several NLRs. These include NOD1/2 (recognizing peptidoglycan fragments) (Martinon et al., 2009Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1863) Google Scholar), NLRP1 (sensing anthrax lethal toxin) (Averette et al., 2009Averette K.M. Pratt M.R. Yang Y. Bassilian S. Whitelegge J.P. Loo J.A. Muir T.W. Bradley K.A. Anthrax lethal toxin induced lysosomal membrane permeabilization and cytosolic cathepsin release is Nlrp1b/Nalp1b-dependent.PLoS ONE. 2009; 4: e7913Crossref PubMed Scopus (47) Google Scholar), NLRP3 (activated by exposure to many pathogens, bacterial RNA, toxins, and crystal structures) (Davis et al., 2011Davis B.K. Wen H. Ting J.P. The inflammasome NLRs in immunity, inflammation, and associated diseases.Annu. Rev. Immunol. 2011; 29: 707-735Crossref PubMed Scopus (1195) Google Scholar; Duewell et al., 2010Duewell P. Kono H. Rayner K.J. Sirois C.M. Vladimer G. Bauernfeind F.G. Abela G.S. Franchi L. Nuñez G. Schnurr M. et al.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361Crossref PubMed Scopus (2570) Google Scholar; Halle et al., 2008Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. Fitzgerald K.A. Latz E. Moore K.J. Golenbock D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.Nat. Immunol. 2008; 9: 857-865Crossref PubMed Scopus (1756) Google Scholar; Hornung et al., 2008Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2159) Google Scholar; Kanneganti et al., 2006Kanneganti T.D. Ozören N. Body-Malapel M. Amer A. Park J.H. Franchi L. Whitfield J. Barchet W. Colonna M. Vandenabeele P. et al.Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.Nature. 2006; 440: 233-236Crossref PubMed Scopus (898) Google Scholar; Sander et al., 2011Sander L.E. Davis M.J. Boekschoten M.V. Amsen D. Dascher C.C. Ryffel B. Swanson J.A. Müller M. Blander J.M. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity.Nature. 2011; 474: 385-389Crossref PubMed Scopus (307) Google Scholar), NLRC4 (sensing of Salmonella, intracellular flagellin and bacterial type III secretion rod proteins) (Franchi et al., 2006Franchi L. Amer A. Body-Malapel M. Kanneganti T.D. Ozören N. Jagirdar R. Inohara N. Vandenabeele P. Bertin J. Coyle A. et al.Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.Nat. Immunol. 2006; 7: 576-582Crossref PubMed Scopus (910) Google Scholar; Miao et al., 2010Miao E.A. Mao D.P. Yudkovsky N. Bonneau R. Lorang C.G. Warren S.E. Leaf I.A. Aderem A. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome.Proc. Natl. Acad. Sci. USA. 2010; 107: 3076-3080Crossref PubMed Scopus (580) Google Scholar), and Naip5 (promoting resistance to Legionella) (Kofoed and Vance, 2011Kofoed E.M. Vance R.E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity.Nature. 2011; 477: 592-595Crossref PubMed Scopus (642) Google Scholar; Molofsky et al., 2006Molofsky A.B. Byrne B.G. Whitfield N.N. Madigan C.A. Fuse E.T. Tateda K. Swanson M.S. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection.J. Exp. Med. 2006; 203: 1093-1104Crossref PubMed Scopus (380) Google Scholar; Ren et al., 2006Ren T. Zamboni D.S. Roy C.R. Dietrich W.F. Vance R.E. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity.PLoS Pathog. 2006; 2: e18Crossref PubMed Scopus (420) Google Scholar). Recent results also suggested a role for NLRP6 in maintenance of bacterial homeostasis in the colon and for NLRP7 in the recognition of lipoproteins (Khare et al., 2012Khare S. Dorfleutner A. Bryan N.B. Yun C. Radian A.D. de Almeida L. Rojanasakul Y. Stehlik C. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages.Immunity. 2012; 36: 464-476Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). NLRP12 (also called Nalp12, Monarch-1, and Pypaf-7) was the first NLR shown in biochemical assays to interact with the adaptor protein Asc to form an active IL-1β-maturing inflammasome (Wang et al., 2002Wang L. Manji G.A. Grenier J.M. Al-Garawi A. Merriam S. Lora J.M. Geddes B.J. Briskin M. DiStefano P.S. Bertin J. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing.J. Biol. Chem. 2002; 277: 29874-29880Crossref PubMed Scopus (301) Google Scholar). The role of NLRP12 in innate immunity has remained unclear. Both inflammatory and inhibitory functions have been suggested, as has a role in hypersensitivity (Allen et al., 2012Allen I.C. Wilson J.E. Schneider M. Lich J.D. Roberts R.A. Arthur J.C. Woodford R.M. Davis B.K. Uronis J.M. Herfarth H.H. et al.NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling.Immunity. 2012; 36: 742-754Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar; Arthur et al., 2010Arthur J.C. Lich J.D. Ye Z. Allen I.C. Gris D. Wilson J.E. Schneider M. Roney K.E. O'Connor B.P. Moore C.B. et al.Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity.J. Immunol. 2010; 185: 4515-4519Crossref PubMed Scopus (114) Google Scholar; Lich and Ting, 2007Lich J.D. Ting J.P. Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions.Microbes Infect. 2007; 9: 672-676Crossref PubMed Scopus (34) Google Scholar; Lich et al., 2007Lich J.D. Williams K.L. Moore C.B. Arthur J.C. Davis B.K. Taxman D.J. Ting J.P. Monarch-1 suppresses non-canonical NF-kappaB activation and p52-dependent chemokine expression in monocytes.J. Immunol. 2007; 178: 1256-1260Crossref PubMed Scopus (157) Google Scholar; Wang et al., 2002Wang L. Manji G.A. Grenier J.M. Al-Garawi A. Merriam S. Lora J.M. Geddes B.J. Briskin M. DiStefano P.S. Bertin J. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing.J. Biol. Chem. 2002; 277: 29874-29880Crossref PubMed Scopus (301) Google Scholar; Zaki et al., 2011Zaki M.H. Vogel P. Malireddi R.K. Body-Malapel M. Anand P.K. Bertin J. Green D.R. Lamkanfi M. Kanneganti T.D. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis.Cancer Cell. 2011; 20: 649-660Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar). Interestingly, like for NLRP3, mutations in NLRP12 are linked to hereditary inflammatory disease (Jéru et al., 2008Jéru I. Duquesnoy P. Fernandes-Alnemri T. Cochet E. Yu J.W. Lackmy-Port-Lis M. Grimprel E. Landman-Parker J. Hentgen V. Marlin S. et al.Mutations in NALP12 cause hereditary periodic fever syndromes.Proc. Natl. Acad. Sci. USA. 2008; 105: 1614-1619Crossref PubMed Scopus (283) Google Scholar), and mutations may lead to increased Asc speckle formation and caspase-1 activity (Jéru et al., 2011bJéru I. Le Borgne G. Cochet E. Hayrapetyan H. Duquesnoy P. Grateau G. Morali A. Sarkisian T. Amselem S. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes.Arthritis Rheum. 2011; 63: 1459-1464Crossref PubMed Scopus (73) Google Scholar). It has been reported that patients carrying NLRP12 mutations associated with increased inflammasome activation have been successfully treated with anti-IL-1 therapy, similar to patients containing mutations in NLRP3 (Hawkins et al., 2003Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N. Engl. J. Med. 2003; 348: 2583-2584Crossref PubMed Scopus (395) Google Scholar; Jéru et al., 2011aJéru I. Hentgen V. Normand S. Duquesnoy P. Cochet E. Delwail A. Grateau G. Marlin S. Amselem S. Lecron J.C. Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy.Arthritis Rheum. 2011; 63: 2142-2148Crossref PubMed Scopus (72) Google Scholar; Lachmann et al., 2009Lachmann H.J. Lowe P. Felix S.D. Rordorf C. Leslie K. Madhoo S. Wittkowski H. Bek S. Hartmann N. Bosset S. et al.In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes.J. Exp. Med. 2009; 206: 1029-1036Crossref PubMed Scopus (243) Google Scholar). No previous studies have addressed the role of NLRP12 in host resistance to infectious agents. Evading innate immunity early in infection plays a key role in virulence of many microorganisms including the plague bacillus Yersinia pestis (Cornelis, 2000Cornelis G.R. Molecular and cell biology aspects of plague.Proc. Natl. Acad. Sci. USA. 2000; 97: 8778-8783Crossref PubMed Scopus (164) Google Scholar; Perry and Fetherston, 1997Perry R.D. Fetherston J.D. Yersinia pestis—etiologic agent of plague.Clin. Microbiol. Rev. 1997; 10: 35-66Crossref PubMed Google Scholar; Stenseth et al., 2008Stenseth N.C. Atshabar B.B. Begon M. Belmain S.R. Bertherat E. Carniel E. Gage K.L. Leirs H. Rahalison L. Plague: past, present, and future.PLoS Med. 2008; 5: e3Crossref PubMed Scopus (346) Google Scholar). This pathogen has several means of minimizing immune activation (Lathem et al., 2007Lathem W.W. Price P.A. Miller V.L. Goldman W.E. A plasminogen-activating protease specifically controls the development of primary pneumonic plague.Science. 2007; 315: 509-513Crossref PubMed Scopus (219) Google Scholar; Monack et al., 1998Monack D.M. Mecsas J. Bouley D. Falkow S. Yersinia-induced apoptosis in vivo aids in the establishment of a systemic infection of mice.J. Exp. Med. 1998; 188: 2127-2137Crossref PubMed Scopus (194) Google Scholar; Mukherjee et al., 2006Mukherjee S. Keitany G. Li Y. Wang Y. Ball H.L. Goldsmith E.J. Orth K. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation.Science. 2006; 312: 1211-1214Crossref PubMed Scopus (464) Google Scholar; Sodeinde et al., 1992Sodeinde O.A. Subrahmanyam Y.V. Stark K. Quan T. Bao Y. Goguen J.D. A surface protease and the invasive character of plague.Science. 1992; 258: 1004-1007Crossref PubMed Scopus (406) Google Scholar; Zhou et al., 2005Zhou H. Monack D.M. Kayagaki N. Wertz I. Yin J. Wolf B. Dixit V.M. Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation.J. Exp. Med. 2005; 202: 1327-1332Crossref PubMed Scopus (193) Google Scholar), with the effect that bacterial replication can proceed with minimal interference by the immune system. As a result, plague is often characterized by very high bacterial numbers in patient sera and organs (Perry and Fetherston, 1997Perry R.D. Fetherston J.D. Yersinia pestis—etiologic agent of plague.Clin. Microbiol. Rev. 1997; 10: 35-66Crossref PubMed Google Scholar). Major factors neutralizing host defenses by active means include a complex type III secretion system (T3SS) (Cornelis, 2002Cornelis G.R. The Yersinia Ysc-Yop ‘type III’ weaponry.Nat. Rev. Mol. Cell Biol. 2002; 3: 742-752Crossref PubMed Scopus (347) Google Scholar; Perry and Fetherston, 1997Perry R.D. Fetherston J.D. Yersinia pestis—etiologic agent of plague.Clin. Microbiol. Rev. 1997; 10: 35-66Crossref PubMed Google Scholar), the plasminogen activator Pla (Lathem et al., 2007Lathem W.W. Price P.A. Miller V.L. Goldman W.E. A plasminogen-activating protease specifically controls the development of primary pneumonic plague.Science. 2007; 315: 509-513Crossref PubMed Scopus (219) Google Scholar; Sodeinde et al., 1992Sodeinde O.A. Subrahmanyam Y.V. Stark K. Quan T. Bao Y. Goguen J.D. A surface protease and the invasive character of plague.Science. 1992; 258: 1004-1007Crossref PubMed Scopus (406) Google Scholar), and a high-affinity iron acquisition system (Perry and Fetherston, 1997Perry R.D. Fetherston J.D. Yersinia pestis—etiologic agent of plague.Clin. Microbiol. Rev. 1997; 10: 35-66Crossref PubMed Google Scholar). The Yersinia T3SS delivers effector proteins, which disrupt signaling within the host cell to prevent phagocytosis, induce apoptosis, and evade the immune response (Cornelis, 2002Cornelis G.R. The Yersinia Ysc-Yop ‘type III’ weaponry.Nat. Rev. Mol. Cell Biol. 2002; 3: 742-752Crossref PubMed Scopus (347) Google Scholar). Many Gram-negative bacteria, including Y. pseudotuberculosis, a very close ancestor of Y. pestis, produce a hexa-acylated lipid A and LPS, which has the potential of strongly triggering innate immunity via Toll-like receptor 4 (TLR4)-MD-2 signaling (Munford, 2008Munford R.S. Sensing gram-negative bacterial lipopolysaccharides: a human disease determinant?.Infect. Immun. 2008; 76: 454-465Crossref PubMed Scopus (143) Google Scholar; Raetz et al., 2007Raetz C.R. Reynolds C.M. Trent M.S. Bishop R.E. Lipid A modification systems in gram-negative bacteria.Annu. Rev. Biochem. 2007; 76: 295-329Crossref PubMed Scopus (923) Google Scholar; Rebeil et al., 2004Rebeil R. Ernst R.K. Gowen B.B. Miller S.I. Hinnebusch B.J. Variation in lipid A structure in the pathogenic yersiniae.Mol. Microbiol. 2004; 52: 1363-1373Crossref PubMed Scopus (211) Google Scholar; Therisod et al., 2002Therisod H. Karibian D. Perry M. Caroff M. Structural analysis of Yersinia pseudotuberculosis ATCC 29833 lipid A.Int. J. Mass Spectrom. 2002; 219: 549-557Crossref Scopus (7) Google Scholar). In contrast, Y. pestis generates a tetra-acylated lipid A-LPS that poorly induces TLR4-mediated cellular activation (Kawahara et al., 2002Kawahara K. Tsukano H. Watanabe H. Lindner B. Matsuura M. Modification of the structure and activity of lipid A in Yersinia pestis lipopolysaccharide by growth temperature.Infect. Immun. 2002; 70: 4092-4098Crossref PubMed Scopus (200) Google Scholar; Knirel et al., 2005Knirel Y.A. Lindner B. Vinogradov E.V. Kocharova N.A. Senchenkova S.N. Shaikhutdinova R.Z. Dentovskaya S.V. Fursova N.K. Bakhteeva I.V. Titareva G.M. et al.Temperature-dependent variations and intraspecies diversity of the structure of the lipopolysaccharide of Yersinia pestis.Biochemistry. 2005; 44: 1731-1743Crossref PubMed Scopus (106) Google Scholar; Montminy et al., 2006Montminy S.W. Khan N. McGrath S. Walkowicz M.J. Sharp F. Conlon J.E. Fukase K. Kusumoto S. Sweet C. Miyake K. et al.Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.Nat. Immunol. 2006; 7: 1066-1073Crossref PubMed Scopus (308) Google Scholar; Rebeil et al., 2006Rebeil R. Ernst R.K. Jarrett C.O. Adams K.N. Miller S.I. Hinnebusch B.J. Characterization of late acyltransferase genes of Yersinia pestis and their role in temperature-dependent lipid A variation.J. Bacteriol. 2006; 188: 1381-1388Crossref PubMed Scopus (78) Google Scholar). We have reported that expression of E. coli lpxL in Y. pestis, which lacks a homolog of this gene, forces the biosynthesis of a hexa-acylated LPS (Montminy et al., 2006Montminy S.W. Khan N. McGrath S. Walkowicz M.J. Sharp F. Conlon J.E. Fukase K. Kusumoto S. Sweet C. Miyake K. et al.Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.Nat. Immunol. 2006; 7: 1066-1073Crossref PubMed Scopus (308) Google Scholar) and that this single modification dramatically reduces virulence in wild-type mice, but not in mice lacking a functional TLR4. This emphasizes that avoiding activation of innate immunity is important for Y. pestis virulence. It also provides a model in which survival is strongly dependent on innate immune defenses, presenting a unique opportunity for evaluating relative importance of innate immunity signals in protection against bacterial infection. One implication of TLR4 engagement is the induction of the immature forms of the central proinflammatory cytokines IL-1β and IL-18. TLR4 signaling can also promote expression of inflammasome components such as Nlrp3 (Bauernfeind et al., 2009Bauernfeind F.G. Horvath G. Stutz A. Alnemri E.S. MacDonald K. Speert D. Fernandes-Alnemri T. Wu J. Monks B.G. Fitzgerald K.A. et al.Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.J. Immunol. 2009; 183: 787-791Crossref PubMed Scopus (1862) Google Scholar). This establishes links between TLR4 activation and the inflammasome pathways. In this study, we have used wild-type Y. pestis and attenuated strains expressing a strong TLR4-activating hexa-acylated LPS as a model system to investigate the involvement of NLRP12 in pathogen recognition and IL-18 - IL-1β release. Here, we show that NLRP12 is an inflammasome component that is central in the recognition of Y. pestis and that IL-18 signaling substantially contributes to resistance against bacteria. Compared to wild-type mice, NLRP12-deficient animals had higher mortality and increased bacterial loads after infection, correlated with lower amounts of IL-18, IL-1β, and IFN-γ. We propose a role for NLRP12 in the sensing of microbial pathogens. We have found that all members of the genus Yersinia other than Y. pestis, and including the very closely related Y. pseudotuberculosis, contain the lpxL gene (S. Paquette et al., unpublished data). Absence of lpxL and the resulting production of a tetra-acylated LPS was proposed to be essential for Y. pestis virulence (Montminy et al., 2006Montminy S.W. Khan N. McGrath S. Walkowicz M.J. Sharp F. Conlon J.E. Fukase K. Kusumoto S. Sweet C. Miyake K. et al.Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.Nat. Immunol. 2006; 7: 1066-1073Crossref PubMed Scopus (308) Google Scholar). To study the evasion of TLR4 signaling in an evolutionary perspective, we cloned lpxL from the closely related Y. pseudotuberculosis and expressed it in Y. pestis, generating Y. pestis-pYtbLpxL, to determine its effects on virulence. Y. pestis grown at 37°C has a tetra-acylated lipid A (Figure S1A available online) (Montminy et al., 2006Montminy S.W. Khan N. McGrath S. Walkowicz M.J. Sharp F. Conlon J.E. Fukase K. Kusumoto S. Sweet C. Miyake K. et al.Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.Nat. Immunol. 2006; 7: 1066-1073Crossref PubMed Scopus (308) Google Scholar), whereas Y. pseudotuberculosis and Y. pestis-pYtbLpxL have a hexa-acylated lipid A (Figure S1B). Mice infected subcutaneously (s.c.) with 500 colony forming units (CFUs) of highly virulent Y. pestis KIM1001 rapidly succumb to infection (Figure 1A). All wild-type mice infected with KIM1001-pYtbLpxL expressing a hexa-acylated Y. pseudotuberculosis-like lipid A survived (Figure 1A), and the animals were protected toward challenge with virulent KIM1001 (Table S1). Survival of mice was strongly TLR4 dependent (Figure 1A). To determine the pathways responsible for in vivo clearance, we infected mice from several strains deficient in inflammatory cytokines or cytokine receptors s.c. with 500 CFUs of KIM1001-pYtbLpxL (Figure 1B). Interestingly, 100% of the animals lacking IL-18 and IL-18R died, as did the TLR4-deficient mice and 70% of the IL-1R1-deficient mice. Weaker effects were observed in animals lacking IFN-αβR, TNFR1, or IL-12p40 (Figure 1B). Resistance to infection in IL-1β- and IL-1R1-deficient animals was reduced to a similar degree, with ∼30% of animals surviving (Figure 1C). However, IL-18 was critically important for resistance to infection in this model, given that IL-18 and IL-18R-deficient mice developed symptoms of bubonic plague and rapidly succumbed to disease when infected with KIM1001-pYtbLpxL (Figures 1B and 1D). Because inflammasomes are responsible for processing of IL-18 and IL-1β into mature forms, this result indicates that this infection model is well-suited for the study of inflammasome mechanisms and implications of IL-18 release. Mice deficient in MyD88, an adaptor molecule common to TLR, IL-1R, and IL-18R signaling pathways, were more susceptible to wild-type Y. pestis KIM1001 than wild-type C57Bl/6 mice (Figure S1C) and are also highly susceptible to strains expressing lpxL (Montminy et al., 2006Montminy S.W. Khan N. McGrath S. Walkowicz M.J. Sharp F. Conlon J.E. Fukase K. Kusumoto S. Sweet C. Miyake K. et al.Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.Nat. Immunol. 2006; 7: 1066-1073Crossref PubMed Scopus (308) Google Scholar). Intravenous (i.v.) infection causes systemic infection even when attenuated bacterial strains are used; hence the inflammatory capacity in tissues for various bacterial strains can better be compared with this route of delivery. We found elevated levels of spleen IL-1β and IL-18 after i.v. infection with Y. pestis and fully virulent KIM1001-induced lower cytokine levels as compared to KIM1001-pYtbLpxL producing the potent LPS (Figures 1E and 1F). A similar release pattern could also be seen in vitro with bone marrow-derived macrophages (BMDMs) (Figure 1G) after stimulation with KIM5 (a pgm mutant attenuated strain used for in vitro experiments) or KIM5-pYtbLpxL. Immunoblot analysis (Figure 1H) indicated that pro-IL-1β was indeed cleaved into mature IL-1β after infection with Y. pestis strains, a sign of inflammasome action. Infection with the Y. pestis-YtbLpxL strain markedly increased levels of pro- and cleaved IL-1β. These results indicate that minimizing inflammasome priming may have been an important implication of lpxL loss during evolution of Y. pestis from Y. pseudotuberculosis. We next wanted to determine which NLRs were involved in resistance to Y. pestis strains and in IL-18 and IL-1β release. NLRP12 and NLRP3 have both been shown to interact with Asc in generating an IL-1β-processing inflamammasome (Agostini et al., 2004Agostini L. Martinon F. Burns K. McDermott M.F. Hawkins P.N. Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.Immunity. 2004; 20: 319-325Abstract Full Text Full Text PDF PubMed Scopus (1379) Google Scholar; Manji et al., 2002Manji G.A. Wang L. Geddes B.J. Brown M. Merriam S. Al-Garawi A. Mak S. Lora J.M. Briskin M. Jurman M. et al.PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B.J. Biol. Chem. 2002; 277: 11570-11575Crossref PubMed Scopus (227) Google Scholar; Wang et al., 2002Wang L. Manji G.A. Grenier J.M. Al-Garawi A. Merriam S. Lora J.M. Geddes B.J. Briskin M. DiStefano P.S. Bertin J. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing.J. Biol. Chem. 2002; 277: 29874-29880Crossref PubMed Scopus (301) Google Scholar), but little is known of the role of NLRP12 during infection. We infected both NLRP3-deficient and NLRP12-deficient mice (Figures 2A and 2B ) s.c. with 500 CFUs of KIM1001-pYtbLpxL and found that only 20% of NLRP12-deficient mice survived the infection, whereas ∼50% of mice lacking NLRP3 survived. This suggests that NLRP12 plays an important role in host defense against some bacterial pathogens. In contrast, NLRP12-deficient mice were resistant to infection with Salmonella typhimurium, whereas TLR4-deficient mice all succumbed to the infectious challenge (Figure 2C). This indicates that NLRP12 deficient animals are not universally more sensitive to infections. The function of NLRP12 is not well understood, but mRNA is detectable in several organs and immune cells (Figures S2A and S2B), including macrophages, although prolonged macrophage maturation led to a decrease in expression (Figure S2C). NLRP12-deficient mice (Figure S2D) had a normal composition of cell populations in spleen and bone marrow (Figure S2E). The possible involvement of NLRP12 in maturation of IL-1β and IL-18 led us to perform in vitro experiments with mouse cells to study inflammasome components that promote caspase-1 cleavage and IL-1β-IL-18 release after infection with Y. pestis and modified strains. Neutrophils express more Nlrp12 than macrophages (Figure S2B), but the role of inflammasomes in pathogen-induced neutrophil release of IL-1β and IL-18 is not yet studied in detail for many microbes. We found that thioglycollate-elicited neutrophil-enriched peritoneal cells released IL-1β after Y. pestis infection (Figure 3A). When compared to cells from wild-type mice, the amounts of IL-1β, but not TNF (Figure S3A) released from the neutrophils lacking NLRP12, were markedly reduced after stimulation with Y. pestis strains. Moreover, infected neutrophils from the caspase-1-deficient mice lack IL-1β in the supernatant, suggesting that Y. pestis-induced neutrophil IL-1β release involves caspase-1 inflammasomes, although we cannot rule out a role for other neutrophil proteases (Netea et al., 2010Netea M.G. Simon A. van de Veerdonk F. Kullberg B.J. Van der Meer J.W. Joosten L.A. IL-1beta processing in host defense: beyond the inflammasomes.PLoS Pathog. 2010; 6: e1000661Crossref PubMed Scopus (383) Google Scholar). It is also unclear which role caspase-11 plays relative to caspase-1 in Y. pestis-induced inflammasome activation, given that the caspase-1-deficient mice utilized in this study contain the same truncated and apparently nonfunctional caspase-11 as previously published (Kayagaki et al., 2011Kayagaki N. Warming S. Lamkanfi M. Vande Walle L. Louie S. Dong J. Newton K. Qu Y. Liu J. Heldens S. et al.Non-canonical inflammasome activation targets caspase-11.Nature. 2011; 479: 117-121Crossref PubMed Scopus (1647) Google Scholar). Macrophages deficient in NLRP12 or NLRP3 also had a reduced ability to release both IL-18 and IL-1β after infection with parental Y. pestis and Y. pestis-pYtbLpxL (Figures 3B and 3C). These observations are consistent with the survival data (Figure 2), which indicated that host recognition of Y. pestis involves NLRP12. Cells deficient in Asc and caspase-1 also had decreased IL-18 and IL-1β release (Figures 3B and 3C). Thus, NLRP12 signaling may occur parallel to or in cooperation with additional inflammasome components because NLRP12 deficie" @default.
• W2028145763 created "2016-06-24" @default.
• W2028145763 creator A5003772429 @default.
• W2028145763 creator A5009373772 @default.
• W2028145763 creator A5011242545 @default.
• W2028145763 creator A5011689503 @default.
• W2028145763 creator A5011977345 @default.
• W2028145763 creator A5013760778 @default.
• W2028145763 creator A5014208965 @default.
• W2028145763 creator A5017897946 @default.
• W2028145763 creator A5028231126 @default.
• W2028145763 creator A5029681288 @default.
• W2028145763 creator A5034107890 @default.
• W2028145763 creator A5045856086 @default.
• W2028145763 creator A5046186975 @default.
• W2028145763 creator A5071375088 @default.
• W2028145763 creator A5074919264 @default.
• W2028145763 creator A5082215179 @default.
• W2028145763 creator A5087535749 @default.
• W2028145763 date "2012-07-01" @default.
• W2028145763 modified "2023-10-10" @default.
• W2028145763 title "The NLRP12 Inflammasome Recognizes Yersinia pestis" @default.
• W2028145763 cites W1790604550 @default.
• W2028145763 cites W1825734539 @default.
• W2028145763 cites W1891980138 @default.
• W2028145763 cites W1969603232 @default.
• W2028145763 cites W1972169896 @default.
• W2028145763 cites W1972483153 @default.
• W2028145763 cites W1974744480 @default.
• W2028145763 cites W1981837371 @default.
• W2028145763 cites W1983053357 @default.
• W2028145763 cites W1988197452 @default.
• W2028145763 cites W1989249407 @default.
• W2028145763 cites W1996264333 @default.
• W2028145763 cites W1998591058 @default.
• W2028145763 cites W2005360556 @default.
• W2028145763 cites W2005473844 @default.
• W2028145763 cites W2006130551 @default.
• W2028145763 cites W2008472051 @default.
• W2028145763 cites W2012193854 @default.
• W2028145763 cites W2012443484 @default.
• W2028145763 cites W2014477644 @default.
• W2028145763 cites W2015316514 @default.
• W2028145763 cites W2029384396 @default.
• W2028145763 cites W2032661113 @default.
• W2028145763 cites W2045953344 @default.
• W2028145763 cites W2048491075 @default.
• W2028145763 cites W2052164279 @default.
• W2028145763 cites W2053114531 @default.
• W2028145763 cites W2055408817 @default.
• W2028145763 cites W2059972136 @default.
• W2028145763 cites W2066318573 @default.
• W2028145763 cites W2069502810 @default.
• W2028145763 cites W2075428144 @default.
• W2028145763 cites W2080827095 @default.
• W2028145763 cites W2095195967 @default.
• W2028145763 cites W2097072854 @default.
• W2028145763 cites W2097298997 @default.
• W2028145763 cites W2104195963 @default.
• W2028145763 cites W2109048203 @default.
• W2028145763 cites W2110348886 @default.
• W2028145763 cites W2111045447 @default.
• W2028145763 cites W2113485094 @default.
• W2028145763 cites W2114315853 @default.
• W2028145763 cites W2114769428 @default.
• W2028145763 cites W2117166589 @default.
• W2028145763 cites W2118403357 @default.
• W2028145763 cites W2119098586 @default.
• W2028145763 cites W2121722333 @default.
• W2028145763 cites W2121828560 @default.
• W2028145763 cites W2126384811 @default.
• W2028145763 cites W2128190429 @default.
• W2028145763 cites W2128657529 @default.
• W2028145763 cites W2132032241 @default.
• W2028145763 cites W2133319714 @default.
• W2028145763 cites W2134735862 @default.
• W2028145763 cites W2137797951 @default.
• W2028145763 cites W2144709035 @default.
• W2028145763 cites W2145638464 @default.
• W2028145763 cites W2145912774 @default.
• W2028145763 cites W2149231090 @default.
• W2028145763 cites W2155538302 @default.
• W2028145763 cites W2157646388 @default.
• W2028145763 cites W2159866361 @default.
• W2028145763 cites W2161320421 @default.
• W2028145763 cites W2166078611 @default.
• W2028145763 cites W2171780940 @default.
• W2028145763 cites W2171831396 @default.
• W2028145763 doi "https://doi.org/10.1016/j.immuni.2012.07.006" @default.
• W2028145763 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3753114" @default.
• W2028145763 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22840842" @default.
• W2028145763 hasPublicationYear "2012" @default.
• W2028145763 type Work @default.
• W2028145763 sameAs 2028145763 @default.
• W2028145763 citedByCount "287" @default.
• W2028145763 countsByYear W20281457632012 @default.
• W2028145763 countsByYear W20281457632013 @default.
• W2028145763 countsByYear W20281457632014 @default.

• next