title: Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1β production in response to β-glucans and the fungal pathogen, Candida albicans.
abstract: Inflammasomes are central mediators of host defense to a wide range of microbial pathogens. The nucleotide-binding domain and leucine-rich repeat containing family (NLR), pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in triggering caspase-1-dependent IL-1β maturation and resistance to fungal dissemination in Candida albicans infection. β-Glucans are major components of fungal cell walls that trigger IL-1β secretion in both murine and human immune cells. In this study, we sought to determine the contribution of β-glucans to C. albicans-induced inflammasome responses in mouse dendritic cells. We show that the NLRP3-apoptosis-associated speck-like protein containing caspase recruitment domain protein-caspase-1 inflammasome is absolutely critical for IL-1β production in response to β-glucans. Interestingly, we also found that both complement receptor 3 (CR3) and dectin-1 play a crucial role in coordinating β-glucan-induced IL-1β processing as well as a cell death response. In addition to the essential role of caspase-1, we identify an important role for the proapoptotic protease caspase-8 in promoting β-glucan-induced cell death and NLRP3 inflammasome-dependent IL-1β maturation. A strong requirement for CR3 and caspase-8 also was found for NLRP3-dependent IL-1β production in response to heat-killed C. albicans. Taken together, these results define the importance of dectin-1, CR3, and caspase-8, in addition to the canonical NLRP3 inflammasome, in mediating β-glucan- and C. albicans-induced innate responses in dendritic cells. Collectively, these findings establish a novel link between β-glucan recognition receptors and the inflammatory proteases caspase-8 and caspase-1 in coordinating cytokine secretion and cell death in response to immunostimulatory fungal components.
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Sandhya
authors: S
authors: Ganesan
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Vijay A K
authors: VAK
authors: Rathinam
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors: Lukas
authors: L
authors: Bossaller
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Kelly
authors: K
authors: Army
authors: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
authors: William J
authors: WJ
authors: Kaiser
authors: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
authors: Edward S
authors: ES
authors: Mocarski
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Christopher P
authors: CP
authors: Dillon
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Douglas R
authors: DR
authors: Green
authors: Center for excellence in Vascular biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Tanya N
authors: TN
authors: Mayadas
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Stuart M
authors: SM
authors: Levitz
authors: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.|Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH, USA.|Department of Medicine, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA.
authors: Amy G
authors: AG
authors: Hise
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Neal
authors: N
authors: Silverman
authors: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Katherine A
authors: KA
authors: Fitzgerald
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000276:immunology*; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D062610:Fungal Polysaccharides / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D047071:beta-Glucans / Q000276:immunology*; D000099181:Dectin-1
chemical_list: D002352:Carrier Proteins; D053181:Caspase 8; D062610:Fungal Polysaccharides; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D047071:beta-Glucans; D000099181:Dectin-1; C587672:IL1B protein, mouse; C492716:Nlrp3 protein, mouse; C505526:Casp8 protein, mouse