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Dectin-1 Mediates the Biological Effects of ß-Glucans

Gordon D. Brown¹, Jurgen Herre¹, David L. Williams², Janet A. Willment¹, Andrew S. J. Marshall¹ and Siamon Gordon¹

¹ Sir William Dunn School of Pathology, Oxford OX1 3RE, United Kingdom
² Department of Surgery, James H. Quillen College of Medicine, Johnson City, TN 37614

Address correspondence to Gordon D. Brown, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, United Kingdom. Phone: 44-1865-27-5522; Fax: 44-1865-27-5515; E-mail: gbrown{at}molbiol.ox.ac.uk

The ability of fungal-derived ß-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF- in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF- in response to fungi, a critical step required for the successful control of these pathogens.

Key Words: ß-glucan receptor • macrophages • inflammation • tumor necrosis factor • Candida

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• Hong, F., Yan, J., Baran, J. T., Allendorf, D. J., Hansen, R. D., Ostroff, G. R., Xing, P. X., Cheung, N.-K. V., Ross, G. D. (2004). Mechanism by Which Orally Administered {beta}-1,3-Glucans Enhance the Tumoricidal Activity of Antitumor Monoclonal Antibodies in Murine Tumor Models. J. Immunol. 173: 797-806 [Abstract] [Full Text]  
• Kropf, P., Freudenberg, N., Kalis, C., Modolell, M., Herath, S., Galanos, C., Freudenberg, M., Muller, I. (2004). Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a role for Toll-like receptor 4 in the control of parasite replication. J. Leukoc. Biol. 76: 48-57 [Abstract] [Full Text]  
• Reid, D. M., Montoya, M., Taylor, P. R., Borrow, P., Gordon, S., Brown, G. D., Wong, S. Y. C. (2004). Expression of the {beta}-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions. J. Leukoc. Biol. 76: 86-94 [Abstract] [Full Text]  
• Takahara, K., Yashima, Y., Omatsu, Y., Yoshida, H., Kimura, Y., Kang, Y.-S., Steinman, R. M., Park, C. G., Inaba, K. (2004). Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin, C-type lectins. Int Immunol 16: 819-829 [Abstract] [Full Text]  
• Borchers, A. T., Keen, C. L., Gershwin, M. E. (2004). Mushrooms, Tumors, and Immunity: An Update. Exp. Biol. Med. 229: 393-406 [Abstract] [Full Text]  
• Netea, M. G., van der Graaf, C., Van der Meer, J. W. M., Kullberg, B. J. (2004). Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system. J. Leukoc. Biol. 75: 749-755 [Abstract] [Full Text]  
• Girotti, M., Evans, J. H., Burke, D., Leslie, C. C. (2004). Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages. J. Biol. Chem. 279: 19113-19121 [Abstract] [Full Text]  
• Marshall, A. S. J., Willment, J. A., Lin, H.-H., Williams, D. L., Gordon, S., Brown, G. D. (2004). Identification and Characterization of a Novel Human Myeloid Inhibitory C-type Lectin-like Receptor (MICL) That Is Predominantly Expressed on Granulocytes and Monocytes. J. Biol. Chem. 279: 14792-14802 [Abstract] [Full Text]  
• Kropf, P., Freudenberg, M. A., Modolell, M., Price, H. P., Herath, S., Antoniazi, S., Galanos, C., Smith, D. F., Muller, I. (2004). Toll-Like Receptor 4 Contributes to Efficient Control of Infection with the Protozoan Parasite Leishmania major. Infect. Immun. 72: 1920-1928 [Abstract] [Full Text]  
• Fraser, I. P., Stuart, L., Ezekowitz, R. A. B. (2004). TLR-independent pattern recognition receptors and anti-inflammatory mechanisms. Innate Immunity 10: 120-124 [Abstract]  
• Diniz, S. N., Nomizo, R., Cisalpino, P. S., Teixeira, M. M., Brown, G. D., Mantovani, A., Gordon, S., Reis, L. F. L., Dias, A. A. M. (2004). PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages. J. Leukoc. Biol. 75: 649-656 [Abstract] [Full Text]  
• Netea, M. G., Sutmuller, R., Hermann, C., Van der Graaf, C. A. A., Van der Meer, J. W. M., van Krieken, J. H., Hartung, T., Adema, G., Kullberg, B. J. (2004). Toll-Like Receptor 2 Suppresses Immunity against Candida albicans through Induction of IL-10 and Regulatory T Cells. J. Immunol. 172: 3712-3718 [Abstract] [Full Text]  
• Lee, H.-K., Dunzendorfer, S., Tobias, P. S. (2004). Cytoplasmic Domain-mediated Dimerizations of Toll-like Receptor 4 Observed by {beta}-Lactamase Enzyme Fragment Complementation. J. Biol. Chem. 279: 10564-10574 [Abstract] [Full Text]  
• Bellocchio, S., Montagnoli, C., Bozza, S., Gaziano, R., Rossi, G., Mambula, S. S., Vecchi, A., Mantovani, A., Levitz, S. M., Romani, L. (2004). The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo. J. Immunol. 172: 3059-3069 [Abstract] [Full Text]  
• Li, C., Ha, T., Kelley, J., Gao, X., Qiu, Y., Kao, R. L, Browder, W., Williams, D. L (2004). Modulating Toll-like receptor mediated signaling by (1->3)-{beta}-D-glucan rapidly induces cardioprotection. Cardiovasc Res 61: 538-547 [Abstract] [Full Text]  
• Taylor, P. R., Brown, G. D., Herre, J., Williams, D. L., Willment, J. A., Gordon, S. (2004). The Role of SIGNR1 and the {beta}-Glucan Receptor (Dectin-1) in the Nonopsonic Recognition of Yeast by Specific Macrophages. J. Immunol. 172: 1157-1162 [Abstract] [Full Text]  

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