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* Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and
Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030
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-
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-B and drive TNF-
induction in murine bone marrow-derived macrophages. However, priming of bone marrow-derived macrophages with GM-CSF or IFN-
permits Dectin-1-CARD9-mediated TNF- induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF- production. Resident peritoneal cells and alveolar macrophages produce TNF- 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- induction.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants to D.M.U. from the National Institutes of Health (AI071116, GM085796) and the American Heart Association (0640100N). H.S.G. holds a Research Fellowship Award from the Crohn’s and Colitis Foundation of America.
2 Address correspondence and reprint requests to Dr. David M. Underhill, Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048. E-mail address: david.underhill{at}cshs.org
3 Abbreviations used in this paper: DC, dendritic cell; CARD, caspase recruitment domain; bmDC, bone marrow-derived DC; bmM, bone marrow-derived macrophage; SBPc, streptavidin binding peptide; TEPM, thioglycollate-elicited peritoneal macrophage; RPC, resident peritoneal cell; AvM, alveolar macrophage; SRE, serum response element; TRITC, tetramethylrhodamine isothiocyanate.
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