title: Fungal zymosan and mannan activate the cryopyrin inflammasome.
abstract: Some fungal species are opportunistic pathogens that can cause infection in people with compromised immune systems. Activation of caspase-1 and the subsequent secretion of mature interleukin (IL)-1beta is a major signaling pathway of the innate immune system, but how yeasts induce caspase-1 activation is unknown. We show here that stimulation of macrophages and dendritic cells with heat-killed Saccharomyces cerevisiae or the purified cell wall components zymosan and mannan induced caspase-1 activation and IL-1beta secretion when combined with ATP. Macrophages deficient for the inflammasome adaptor ASC were defective in caspase-1 activation and IL-1beta secretion, suggesting involvement of an ASC-dependent inflammasome. Indeed, caspase-1 activation was abrogated in macrophages lacking the NOD-like (NLR) protein Cryopyrin/Nalp3 and in wild type macrophages pretreated with the pannexin-1 inhibitor probenecid. IL-1beta secretion further required the Toll-like receptor (TLR) adaptors MyD88 and TRIF, and partially relied on TLR2. We previously showed that bacterial molecules such as lipopolysaccharide (LPS) and peptidoglycan induce activation of caspase-7 through the Cryopyrin inflammasome. Similarly, Cryopyrin and ASC were required for activation of caspase-7 in macrophages stimulated with zymosan or mannan and ATP. These results demonstrate that the conserved fungal components zymosan and mannan require ASC and Cryopyrin for caspase-1 activation and IL-1beta secretion and suggest an important role for the Cryopyrin inflammasome during fungal infections.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: R K Subbarao
authors.initials: RK
authors.lastname: Malireddi
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006358:Hot Temperature; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008351:Mannans / Q000494:pharmacology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017630:Connexins; D053583:Interleukin-1beta; D008351:Mannans; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; C492716:Nlrp3 protein, mouse; C503631:Panx1 protein, mouse; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate; D015054:Zymosan; D053179:Caspase 7; D020170:Caspase 1