Journal of Clinical Immunology

, Volume 30, Issue 4, pp 496–501

ITAM Receptor Signaling and the NLRP3 Inflammasome in Antifungal Immunity




Infections with fungi can cause systemic life-threatening diseases in immunocompromised individuals like cancer or AIDS patients. Recent work has uncovered essential roles for C-type lectin pattern recognition receptors, spleen tyrosine kinase (SYK) and the cytosolic NLRP3 inflammasome in innate antifungal immunity. Upon fungal infection, SYK is activated by several ITAM-containing or ITAM-coupled C-type lectin receptors on myeloid cells leading to the production of pro-inflammatory cytokines including IL-1β to initiate antifungal responses. Mature IL-1β production requires in addition to the synthesis of pro-IL-1β a cleavage of the precursor protein by the inflammatory Caspase-1 which is controlled within the NLRP3 inflammasome.


Here, we discuss how ITAM receptor signaling and NLRP3 cooperate for the induction of antifungal immunity.


ITAM receptors SYK CARD9 inflammasome NLRP3 IL-1β 


  1. 1.
    Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.CrossRefPubMedGoogle Scholar
  2. 2.
    Yu HB, Finlay BB. The caspase-1 inflammasome: a pilot of innate immune responses. Cell Host Microbe. 2008;4:198–208.CrossRefPubMedGoogle Scholar
  3. 3.
    Pedra JH, Cassel SL, Sutterwala FS. Sensing pathogens and danger signals by the inflammasome. Curr Opin Immunol. 2009;21:10–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Burckstummer T, Baumann C, Bluml S, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10:266–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–13.CrossRefPubMedGoogle Scholar
  6. 6.
    Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Roberts TL, Idris A, Dunn JA, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science. 2009;323:1057–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Poeck H, Bscheider M, Gross O, et al (2010). Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol. 11:63–9.Google Scholar
  9. 9.
    Gross O, Poeck H, Bscheider M, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009;459:433–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Hise AG, Tomalka J, Ganesan S, et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe. 2009;5:487–97.CrossRefPubMedGoogle Scholar
  11. 11.
    Joly S, Ma N, Sadler JJ, Soll DR, Cassel SL, Sutterwala FS (2009). Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J Immunol 183:3578–81.Google Scholar
  12. 12.
    Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Hornung V, Bauernfeind F, Halle A, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.CrossRefPubMedGoogle Scholar
  14. 14.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Kanneganti TD, Ozoren N, Body-Malapel M, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440:233–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Mariathasan S, Weiss DS, Newton K, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.CrossRefPubMedGoogle Scholar
  17. 17.
    Muruve DA, Petrilli V, Zaiss AK, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452:103–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Allen IC, Scull MA, Moore CB, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza a virus through recognition of viral RNA. Immunity. 2009;30:556–65.CrossRefPubMedGoogle Scholar
  19. 19.
    Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009;206:79–87.CrossRefPubMedGoogle Scholar
  20. 20.
    Thomas PG, Dash P, Aldridge Jr JR, et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity. 2009;30:566–75.CrossRefPubMedGoogle Scholar
  21. 21.
    Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453:1122–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Halle A, Hornung V, Petzold GC, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Duncan JA, Bergstralh DT, Wang Y, et al. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A. 2007;104:8041–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.CrossRefPubMedGoogle Scholar
  25. 25.
    Vonk AG, Netea MG, van Krieken JH, Iwakura Y, van der Meer JW, Kullberg BJ. Endogenous interleukin (IL)-1 alpha and IL-1 beta are crucial for host defense against disseminated candidiasis. J Infect Dis. 2006;193:1419–26.CrossRefPubMedGoogle Scholar
  26. 26.
    Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008;1143:1–20.CrossRefPubMedGoogle Scholar
  27. 27.
    Brown GD. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol. 2006;6:33–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Robinson MJ, Osorio F, Rosas M, et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J Exp Med. 2009;206:2037–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Rogers NC, Slack EC, Edwards AD, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22:507–17.CrossRefPubMedGoogle Scholar
  30. 30.
    Wells CA, Salvage-Jones JA, Li X, et al. The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J Immunol. 2008;180:7404–13.PubMedGoogle Scholar
  31. 31.
    Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol. 2009;9:465–79.CrossRefPubMedGoogle Scholar
  32. 32.
    Gross O, Gewies A, Finger K, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006;442:651–6.CrossRefPubMedGoogle Scholar
  33. 33.
    LeibundGut-Landmann S, Gross O, Robinson MJ, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8:630–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Underhill DM, Rossnagle E, Lowell CA, Simmons RM. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 2005;106:2543–50.CrossRefPubMedGoogle Scholar
  35. 35.
    Goodridge HS, Shimada T, Wolf AJ, et al. Differential use of CARD9 by dectin-1 in macrophages and dendritic cells. J Immunol. 2009;182:1146–54.PubMedGoogle Scholar
  36. 36.
    Hara H, Ishihara C, Takeuchi A, et al. Cell type-specific regulation of ITAM-mediated NF-kappaB activation by the adaptors, CARMA1 and CARD9. J Immunol. 2008;181:918–30.PubMedGoogle Scholar
  37. 37.
    Hara H, Ishihara C, Takeuchi A, et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat Immunol. 2007;8:619–29.CrossRefPubMedGoogle Scholar
  38. 38.
    Hara H, Saito T. CARD9 versus CARMA1 in innate and adaptive immunity. Trends Immunol. 2009;30:234–42.CrossRefPubMedGoogle Scholar
  39. 39.
    Gringhuis SI, den Dunnen J, Litjens M, et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat Immunol. 2009;10:203–13.CrossRefPubMedGoogle Scholar
  40. 40.
    Taylor PR, Tsoni SV, Willment JA, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. 2007;8:31–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Tsoni SV, Brown GD. beta-Glucans and dectin-1. Ann N Y Acad Sci. 2008;1143:45–60.CrossRefPubMedGoogle Scholar
  42. 42.
    Ferwerda B, Ferwerda G, Plantinga TS, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009;361:1760–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Glocker EO, Hennigs A, Nabavi M, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361:1727–35.CrossRefPubMedGoogle Scholar
  44. 44.
    McGreal EP, Rosas M, Brown GD, et al. The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology. 2006;16:422–30.CrossRefPubMedGoogle Scholar
  45. 45.
    Barrett NA, Maekawa A, Rahman OM, Austen KF, Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells. J Immunol. 2009;182:1119–28.PubMedGoogle Scholar
  46. 46.
    Romani L. Immunity to fungal infections. Nat Rev Immunol. 2004;4:1–23.CrossRefPubMedGoogle Scholar
  47. 47.
    Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14:1583–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Tschopp J, Schroder K (2010). NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 10:210–5.Google Scholar
  49. 49.
    Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J (2010). Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–40.Google Scholar
  50. 50.
    Bauernfeind FG, Horvath G, Stutz A, et al (2009). Cutting edge: NF-{kappa}B activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–91.Google Scholar
  51. 51.
    Kumar H, Kumagai Y, Tsuchida T, et al. Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal beta-glucan. J Immunol. 2009;183:8061–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Lamkanfi M, Malireddi RK, Kanneganti TD. Fungal zymosan and mannan activate the cryopyrin inflammasome. J Biol Chem. 2009;284:20574–81.CrossRefPubMedGoogle Scholar
  53. 53.
    Ng G, Sharma K, Ward SM, et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity. 2008;29:807–18.CrossRefPubMedGoogle Scholar
  54. 54.
    Tiemi Shio M, Eisenbarth SC, Savaria M, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 2009;5:e1000559.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.III. Medizinische Klinik, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany
  2. 2.Laboratory of Signaling in the Immune System, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthNeuherbergGermany

Personalised recommendations