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Fungal zymosan and mannan activate the cryopyrin inflammasome

Mohamed Lamkanfi1, R K Subbarao Malireddi, Thirumala-Devi Kanneganti

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

The Journal of Biological Chemistry
|June 11, 2009
PubMed

Insights

Fungal components like zymosan and mannan trigger caspase-1 activation and IL-1beta secretion via the Cryopyrin inflammasome. This innate immune pathway is crucial for responding to fungal infections in immune cells.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Opportunistic fungal infections pose risks to immunocompromised individuals.
  • The innate immune system's caspase-1/interleukin-1beta pathway is vital but its fungal induction mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which fungal components induce caspase-1 activation and IL-1beta secretion.
  • To identify the specific inflammasome components and signaling pathways involved in the yeast-induced immune response.

Main Methods:

  • Stimulation of macrophages and dendritic cells with heat-killed Saccharomyces cerevisiae, zymosan, and mannan.
  • Assessment of caspase-1 activation and IL-1beta secretion in wild-type and inflammasome-deficient cells (e.g., ASC-deficient, Cryopyrin/Nalp3-deficient).
  • Inhibition studies using probenecid and evaluation of Toll-like receptor (TLR) adaptor involvement (MyD88, TRIF, TLR2).

Main Results:

  • Zymosan and mannan, with ATP, induced caspase-1 activation and IL-1beta secretion in immune cells.
  • ASC-dependent inflammasome activation was essential, specifically involving Cryopyrin/Nalp3.
  • IL-1beta secretion required TLR adaptors MyD88 and TRIF, with partial reliance on TLR2.
  • Cryopyrin and ASC were also necessary for zymosan/mannan-induced caspase-7 activation.

Conclusions:

  • Conserved fungal components zymosan and mannan activate the ASC and Cryopyrin-dependent inflammasome.
  • This pathway is critical for initiating caspase-1 and caspase-7 activation and IL-1beta secretion in response to fungal stimuli.
  • The Cryopyrin inflammasome plays a significant role in the host's innate immune defense against fungal infections.

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