title: Differential use of CARD9 by dectin-1 in macrophages and dendritic cells.
abstract: The pattern recognition receptors TLR2 and Dectin-1 play key roles in coordinating the responses of macrophages and dendritic cells (DC) to fungi. Induction of proinflammatory cytokines is instructed by signals from both TLR2 and Dectin-1. A recent report identified a role for CARD9 in innate anti-fungal responses, demonstrating CARD9-Bcl10-mediated activation of NF-kappaB and proinflammatory cytokine induction in murine bone marrow-derived DC stimulated via Dectin-1. We now report that Dectin-1-CARD9 signals fail to activate NF-kappaB and drive TNF-alpha induction in murine bone marrow-derived macrophages. However, priming of bone marrow-derived macrophages with GM-CSF or IFN-gamma permits Dectin-1-CARD9-mediated TNF-alpha induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF-alpha production. Resident peritoneal cells and alveolar macrophages produce TNF-alpha upon Dectin-1 ligation, while thioglycollate-elicited peritoneal macrophages and Flt3L-derived DC do not. We present data demonstrating that CARD9 is recruited to phagosomes via its CARD domain where it enhances TLR-induced cytokine production even in cells in which Dectin-1 is insufficient to drive cytokine production. In such cells, Dectin-1, CARD9, and Bcl10 levels are not limiting, and data indicate that these cells express additional factors that restrict Dectin-1-CARD9 signaling for TNF-alpha induction.
authors.affiliation: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Goodridge
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimada
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Wolf
authors.forename: Yen-Michael S
authors.initials: YM
authors.lastname: Hsu
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Becker
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: David M
authors.initials: DM
authors.lastname: Underhill
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010588:Phagosomes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099181:Dectin-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000099181:Dectin-1; C488088:Bcl10 protein, mouse; C513280:Card9 protein, mouse