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The Induction of Inflammation by Dectin-1 In Vivo Is Dependent on Myeloid Cell Programming and the Progression of Phagocytosis¹

Marcela Rosas^2,*, Kate Liddiard^2,*, Matti Kimberg, Inês Faro-Trindade, Jacqueline U. McDonald^*, David L. Williams, Gordon D. Brown and Philip R. Taylor^3,*

^* Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, United Kingdom; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; and Department of Surgery, James H. Quillen College of Medicine, Johnson City, TN 37614

Dectin-1 is the archetypal signaling, non-Toll-like pattern recognition receptor that plays a protective role in immune defense to Candida albicans as the major leukocyte receptor for β-glucans. Dectin-1-deficiency is associated with impaired recruitment of inflammatory leukocytes and inflammatory mediator production at the site of infection. In this study, we have used mice to define the mechanisms that regulate the dectin-1-mediated inflammatory responses. Myeloid cell activation by dectin-1 is controlled by inherent cellular programming, with distinct macrophage and dendritic cell populations responding differentially to the engagement of this receptor. The inflammatory response is further modulated by the progression of the phagocytosis, with "frustrated phagocytosis" resulting in dramatically augmented inflammatory responses. These studies demonstrate that dectin-1 in isolation is sufficient to drive a potent inflammatory response in a context-dependent manner. This has implications for the mechanism by which myeloid cells are activated during fungal infections and the processes involved in the therapeutic manipulation of the immune system via exogenous dectin-1 stimulation or blockade.

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 P.R.T. is the recipient of a Medical Research Council Senior Research Fellowship (G0601617) and G.D.B. is the recipient of a Wellcome Trust International Senior Research Fellowship. This work was also funded in part by Wellcome Trust Project Grant 070579 (to P.R.T.) and National Institutes of Health/National Institute of General Medical Sciences Grant 53522 (to D.L.W.).

² M.R. and K.L. contributed equally to the study.

³ Address correspondence and reprint requests to Dr. Philip Taylor, Medical Biochemistry and Immunology, Cardiff University School of Medicine, Tenovus Building, Heath Park, Cardiff, CF14 4XN, U.K. E-mail address: TaylorPR{at}Cardiff.ac.uk

⁴ Abbreviations used in this paper: MØ, macrophage; BMMØ, bone marrow-derived MØ; BMDC, bone marrow-derived dendritic cell; Curd-mp, curdlan microparticle; DC, dendritic cell; Glu-mp, glucan microparticle; MØP, MØ progenitor.