Differential use of CARD9 by dectin-1 in macrophages and dendritic cells

J Immunol. 2009 Jan 15;182(2):1146-54. doi: 10.4049/jimmunol.182.2.1146.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • Bone Marrow Cells / enzymology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • CARD Signaling Adaptor Proteins
  • Cell Line
  • Cells, Cultured
  • Dendritic Cells / enzymology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Humans
  • Lectins, C-Type
  • Macrophages, Alveolar / enzymology
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Peritoneal / enzymology
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism*
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / physiology*
  • Phagosomes / enzymology
  • Phagosomes / immunology
  • Phagosomes / metabolism
  • Protein Structure, Tertiary
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptors / physiology
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card9 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • dectin 1