Differential Use of CARD9 by Dectin-1 in Macrophages and Dendritic Cells

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-kappa B 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-kappa B 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 thioglycol-late-elicited peritoneal macrophages and FIt3L-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. The Journal of Immunology, 2009, 182: 1146-1154.