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. 2012 Mar 17;3(2):98–105. doi: 10.1007/s13238-012-2028-3

Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation

Yi-Nan Gong 1, Feng Shao 2,✉
PMCID: PMC4875417  PMID: 22426978

Abstract

The inflammasome is an emerging new pathway in innate immune defense against microbial infection or endogenous danger signals. The inflammasome stimulates activation of inflammatory caspases, mainly caspase-1. Caspase-1 activation is responsible for processing and secretion of IL-1β and IL-18 as well as for inducing macrophage pyroptotic death. Assembly of the large cytoplasmic inflammasome complex is thought to be mediated by members of NOD-like receptor (NLR) family. While functions of most of the NLR proteins remain to be defined, several NLR proteins including NLRC4 have been shown to assemble distinct inflammasome complexes. These inflammasome pathways, particularly the NLRC4 inflammasome, play a critical role in sensing and restricting diverse types of bacterial infections. Here we review recent advances in defining the exact bacterial ligands and the ligand-binding receptors involved in NLRC4 inflammasome activation. Implications of the discovery of the NAIP family of inflammasome receptors for bacterial flagellin and type III secretion apparatus on future inflammasome and bacterial infection studies are also discussed.

Keywords: inflammasome, NOD-like receptors, NLRC4, caspase-1, NAIP, type III secretion system, flagellin, Salmonella, Legionella, enteropathogenic E. coli, Burkholderia

References

  1. Amer A., Franchi L., Kanneganti T.D., Body-Malapel M., Ozören N., Brady G., Meshinchi S., Jagirdar R., Gewirtz A., Akira S., et al. Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J Biol Chem. 2006;281:35217–35223. doi: 10.1074/jbc.M604933200. [DOI] [PubMed] [Google Scholar]
  2. Anand, P.K., Malireddi, R.K., and Kanneganti, T.D. (2011). Role of the nlrp3 inflammasome in microbial infection. Front Microbiol 2,. [DOI] [PMC free article] [PubMed]
  3. Boyden E.D., Dietrich W.F. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006;38:240–244. doi: 10.1038/ng1724. [DOI] [PubMed] [Google Scholar]
  4. Brodsky I.E., Medzhitov R. Pyroptosis: macrophage suicide exposes hidden invaders. Curr Biol. 2011;21:R72–R75. doi: 10.1016/j.cub.2010.12.008. [DOI] [PubMed] [Google Scholar]
  5. Broz P., Newton K., Lamkanfi M., Mariathasan S., Dixit V.M., Monack D.M. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med. 2010;207:1745–1755. doi: 10.1084/jem.20100257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Broz P., von Moltke J., Jones J.W., Vance R.E., Monack D.M. Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe. 2010;8:471–483. doi: 10.1016/j.chom.2010.11.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Case C.L., Shin S., Roy C.R. Asc and Ipaf Inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila. Infect Immun. 2009;77:1981–1991. doi: 10.1128/IAI.01382-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen G., Shaw M.H., Kim Y.G., Nuñez G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol. 2009;4:365–398. doi: 10.1146/annurev.pathol.4.110807.092239. [DOI] [PubMed] [Google Scholar]
  9. Chen G.Y., Liu M., Wang F., Bertin J., Núñez G. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J Immunol. 2011;186:7187–7194. doi: 10.4049/jimmunol.1100412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chen L.M., Kaniga K., Galán J.E. Salmonella spp. are cytotoxic for cultured macrophages. Mol Microbiol. 1996;21:1101–1115. doi: 10.1046/j.1365-2958.1996.471410.x. [DOI] [PubMed] [Google Scholar]
  11. Cornelis G.R. The type III secretion injectisome, a complex nanomachine for intracellular ‘toxin’ delivery. Biol Chem. 2010;391:745–751. doi: 10.1515/bc.2010.079. [DOI] [PubMed] [Google Scholar]
  12. Cui J., Shao F. Biochemistry and cell signaling taught by bacterial effectors. Trends Biochem Sci. 2011;36:532–540. doi: 10.1016/j.tibs.2011.07.003. [DOI] [PubMed] [Google Scholar]
  13. Davis B.K., Wen H., Ting J.P. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–735. doi: 10.1146/annurev-immunol-031210-101405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Deane J.E., Roversi P., Cordes F.S., Johnson S., Kenjale R., Daniell S., Booy F., Picking W.D., Picking W.L., Blocker A.J., et al. Molecular model of a type III secretion system needle: Implications for host-cell sensing. Proc Natl Acad Sci U S A. 2006;103:12529–12533. doi: 10.1073/pnas.0602689103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Derré I., Isberg R.R. Macrophages from mice with the restrictive Lgn1 allele exhibit multifactorial resistance to Legionella pneumophila. Infect Immun. 2004;72:6221–6229. doi: 10.1128/IAI.72.11.6221-6229.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Diez E., Lee S.H., Gauthier S., Yaraghi Z., Tremblay M., Vidal S., Gros P. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat Genet. 2003;33:55–60. doi: 10.1038/ng1065. [DOI] [PubMed] [Google Scholar]
  17. Duncan J.A., Bergstralh D.T., Wang Y., Willingham S.B., Ye Z., Zimmermann A.G., Ting J.P. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A. 2007;104:8041–8046. doi: 10.1073/pnas.0611496104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Elinav E., Strowig T., Kau A.L., Henao-Mejia J., Thaiss C.A., Booth C.J., Peaper D.R., Bertin J., Eisenbarth S.C., Gordon J.I., et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145:745–757. doi: 10.1016/j.cell.2011.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Erhardt M., Namba K., Hughes K.T. Bacterial nanomachines: the flagellum and type III injectisome. Cold Spring Harb Perspect Biol. 2010;2:a000299. doi: 10.1101/cshperspect.a000299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Faustin B., Lartigue L., Bruey J.M., Luciano F., Sergienko E., Bailly-Maitre B., Volkmann N., Hanein D., Rouiller I., Reed J.C. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007;25:713–724. doi: 10.1016/j.molcel.2007.01.032. [DOI] [PubMed] [Google Scholar]
  21. Fink S.L., Cookson B.T. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol. 2006;8:1812–1825. doi: 10.1111/j.1462-5822.2006.00751.x. [DOI] [PubMed] [Google Scholar]
  22. Fortier A., de Chastellier C., Balor S., Gros P. Birc1e/Naip5 rapidly antagonizes modulation of phagosome maturation by Legionella pneumophila. Cell Microbiol. 2007;9:910–923. doi: 10.1111/j.1462-5822.2006.00839.x. [DOI] [PubMed] [Google Scholar]
  23. Fortier A., Doiron K., Saleh M., Grinstein S., Gros P. Restriction of Legionella pneumophila replication in macrophages requires concerted action of the transcriptional regulators Irf1 and Irf8 and nod-like receptors Naip5 and Nlrc4. Infect Immun. 2009;77:4794–4805. doi: 10.1128/IAI.01546-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Franchi 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;7:576–582. doi: 10.1038/ni1346. [DOI] [PubMed] [Google Scholar]
  25. Franchi L., Stoolman J., Kanneganti T.D., Verma A., Ramphal R., Núñez G. Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation. Eur J Immunol. 2007;37:3030–3039. doi: 10.1002/eji.200737532. [DOI] [PubMed] [Google Scholar]
  26. Galán J.E., Wolf-Watz H. Protein delivery into eukaryotic cells by type III secretion machines. Nature. 2006;444:567–573. doi: 10.1038/nature05272. [DOI] [PubMed] [Google Scholar]
  27. Galle M., Schotte P., Haegman M., Wullaert A., Yang H.J., Jin S., Beyaert R. The Pseudomonas aeruginosa Type III secretion system plays a dual role in the regulation of caspase-1 mediated IL-1beta maturation. J Cell Mol Med. 2008;12:1767–1776. doi: 10.1111/j.1582-4934.2007.00190.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ge J., Shao F. Manipulation of host vesicular trafficking and innate immune defense by Legionella Dot/Icm effectors. Cell Microbiol. 2011;13:1870–1880. doi: 10.1111/j.1462-5822.2011.01710.x. [DOI] [PubMed] [Google Scholar]
  29. Hersh D., Monack D.M., Smith M.R., Ghori N., Falkow S., Zychlinsky A. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci U S A. 1999;96:2396–2401. doi: 10.1073/pnas.96.5.2396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hornung V., Latz E. Intracellular DNA recognition. Nat Rev Immunol. 2010;10:123–130. doi: 10.1038/nri2690. [DOI] [PubMed] [Google Scholar]
  31. Isberg R.R., O’Connor T.J., Heidtman M. The Legionella pneumophila replication vacuole: making a cosy niche inside host cells. Nat Rev Microbiol. 2009;7:13–24. doi: 10.1038/nrmicro1967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kofoed E.M., Vance R.E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature. 2011;477:592–595. doi: 10.1038/nature10394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lamkanfi M., Amer A., Kanneganti T.D., Muñoz-Planillo R., Chen G., Vandenabeele P., Fortier A., Gros P., Núñez G. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J Immunol. 2007;178:8022–8027. doi: 10.4049/jimmunol.178.12.8022. [DOI] [PubMed] [Google Scholar]
  34. Lightfield K.L., Persson J., Brubaker S.W., Witte C.E., von Moltke J., Dunipace E.A., Henry T., Sun Y.H., Cado D., Dietrich W.F., et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol. 2008;9:1171–1178. doi: 10.1038/ni.1646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mariathasan S., Newton K., Monack D.M., Vucic D., French D.M., Lee W.P., Roose-Girma M., Erickson S., Dixit V.M. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430:213–218. doi: 10.1038/nature02664. [DOI] [PubMed] [Google Scholar]
  36. Marlovits T.C., Kubori T., Lara-Tejero M., Thomas D., Unger V.M., Galán J.E. Assembly of the inner rod determines needle length in the type III secretion injectisome. Nature. 2006;441:637–640. doi: 10.1038/nature04822. [DOI] [PubMed] [Google Scholar]
  37. Master S.S., Rampini S.K., Davis A.S., Keller C., Ehlers S., Springer B., Timmins G.S., Sander P., Deretic V. Mycobacterium tuberculosis prevents inflammasome activation. Cell Host Microbe. 2008;3:224–232. doi: 10.1016/j.chom.2008.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Miao E.A., Alpuche-Aranda C.M., Dors M., Clark A.E., Bader M.W., Miller S.I., Aderem A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006;7:569–575. doi: 10.1038/ni1344. [DOI] [PubMed] [Google Scholar]
  39. Miao E.A., Ernst R.K., Dors M., Mao D.P., Aderem A. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci U S A. 2008;105:2562–2567. doi: 10.1073/pnas.0712183105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Miao E.A., Leaf I.A., Treuting P.M., Mao D.P., Dors M., Sarkar A., Warren S.E., Wewers M.D., Aderem A. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol. 2010;11:1136–1142. doi: 10.1038/ni.1960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Miao 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 U S A. 2010;107:3076–3080. doi: 10.1073/pnas.0913087107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Miao E.A., Warren S.E. Innate immune detection of bacterial virulence factors via the NLRC4 inflammasome. J Clin Immunol. 2010;30:502–506. doi: 10.1007/s10875-010-9386-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Molofsky 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;203:1093–1104. doi: 10.1084/jem.20051659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ren 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:e18. doi: 10.1371/journal.ppat.0020018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schroder K., Tschopp J. The inflammasomes. Cell. 2010;140:821–832. doi: 10.1016/j.cell.2010.01.040. [DOI] [PubMed] [Google Scholar]
  46. Subramanian N., Qadri A. Lysophospholipid sensing triggers secretion of flagellin from pathogenic salmonella. Nat Immunol. 2006;7:583–589. doi: 10.1038/ni1336. [DOI] [PubMed] [Google Scholar]
  47. Sun Y.H., Rolán H.G., Tsolis R.M. Injection of flagellin into the host cell cytosol by Salmonella enterica serotype Typhimurium. J Biol Chem. 2007;282:33897–33901. doi: 10.1074/jbc.C700181200. [DOI] [PubMed] [Google Scholar]
  48. Sutterwala F.S., Mijares L.A., Li L., Ogura Y., Kazmierczak B.I., Flavell R.A. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med. 2007;204:3235–3245. doi: 10.1084/jem.20071239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Takeuchi O., Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–820. doi: 10.1016/j.cell.2010.01.022. [DOI] [PubMed] [Google Scholar]
  50. Ting J.P., Kastner D.L., Hoffman H.M. CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol. 2006;6:183–195. doi: 10.1038/nri1788. [DOI] [PubMed] [Google Scholar]
  51. Tsuchiya K., Hara H., Kawamura I., Nomura T., Yamamoto T., Daim S., Dewamitta S.R., Shen Y., Fang R., Mitsuyama M. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J Immunol. 2010;185:1186–1195. doi: 10.4049/jimmunol.1001058. [DOI] [PubMed] [Google Scholar]
  52. Warren S.E., Mao D.P., Rodriguez A.E., Miao E.A., Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol. 2008;180:7558–7564. doi: 10.4049/jimmunol.180.11.7558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wright E.K., Goodart S.A., Growney J.D., Hadinoto V., Endrizzi M.G., Long E.M., Sadigh K., Abney A.L., Bernstein-Hanley I., Dietrich W.F. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol. 2003;13:27–36. doi: 10.1016/S0960-9822(02)01359-3. [DOI] [PubMed] [Google Scholar]
  54. Wu J., Fernandes-Alnemri T., Alnemri E.S. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J Clin Immunol. 2010;30:693–702. doi: 10.1007/s10875-010-9425-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Zamboni D.S., Kobayashi K.S., Kohlsdorf T., Ogura Y., Long E.M., Vance R.E., Kuida K., Mariathasan S., Dixit V.M., Flavell R.A., et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol. 2006;7:318–325. doi: 10.1038/ni1305. [DOI] [PubMed] [Google Scholar]
  56. Zhao Y., Yang J., Shi J., Gong Y.N., Lu Q., Xu H., Liu L., Shao F. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature. 2011;477:596–600. doi: 10.1038/nature10510. [DOI] [PubMed] [Google Scholar]

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