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MyD88-Dependent Activation of B220^–CD11b⁺LY-6C⁺ Dendritic Cells during Brucella melitensis Infection¹

Richard Copin^*, Patrick De Baetselier, Yves Carlier, Jean-Jacques Letesson^2,3,* and Eric Muraille^2,3,

^* Unité de Recherche en Biologie Moléculaire, Laboratoire d’Immunologie et de Microbiologie, Faculté Universitaire Notre Dame de la Paix, Namur, Belgium; Laboratoire de Parasitologie, Faculté de Médecine, Université Libre de Bruxelles, Bruxelles, Belgium; and Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Vrije Universiteit Brussel, Brussels, Belgium

IFN- is a key cytokine controlling Brucella infection. One of its major function is the stimulation of Brucella-killing effector mechanisms, such as inducible NO synthase (iNOS)/NOS2 activity, in phagocytic cells. In this study, an attempt to identify the main cellular components of the immune response induced by Brucella melitensis in vivo is made. IFN- and iNOS protein were analyzed intracellularly using flow cytometry in chronically infected mice. Although TCR⁺CD4⁺ cells were the predominant source of IFN- in the spleen, we also identified CD11b⁺LY-6C⁺LY-6G^–MHC-II⁺ cells as the main iNOS-producing cells in the spleen and the peritoneal cavity. These cells appear similar to inflammatory dendritic cells recently described in the mouse model of Listeria monocytogenes infection and human psoriasis: the TNF/iNOS-producing dendritic cells. Using genetically deficient mice, we demonstrated that the induction of iNOS and IFN--producing cells due to Brucella infection required TLR4 and TLR9 stimulation coupled to Myd88-dependent signaling pathways. The unique role of MyD88 was confirmed by the lack of impact of Toll-IL-1R domain-containing adaptor inducing IFN- deficiency. The reduction of IFN-⁺ and iNOS⁺ cell frequency observed in MyD88-, TLR4-, and TLR9-deficient mice correlated with a proportional lack of Brucella growth control. Taken together, our results provide new insight into how immune responses fight Brucella infection.

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 from the Fond National de la Recherche Scientifique (FNRS; Convention Fonds de la Recherche Scientifique Médicale FNRS 3.4.600.06.F, Belgium), the Fond Emile Defay (Belgium), and the Fond Van Buuren (Belgium). E.M. is "Chercheur Qualifié du FNRS."

² J.-J.L. and E.M. should be considered equally as last authors.

³ Address correspondence and reprint requests to Dr. Eric Muraille, Laboratoire de Parasitologie, Faculté de médecine, Route de Lennik 808, Université Libre de Bruxelles, 1070 Bruxelles, Belgium; E-mail address: emuraille{at}hotmail.com or Dr. Jean-Jacques Letesson, Unité de Recherche en Biologie Moléculaire, Laboratoire d’Immunologie et de Microbiologie, Université de Namur, Rue de Bruxelles 61, 5000 Namur, Belgium; E-mail address: jean-jacques.letesson{at}fundp.ac.be

⁴ Abbreviations used in this paper: RNI, reactive nitrogen intermediate; ROI, reactive oxygen intermediate; iNOS, inducible NO synthase; PAMP, pathogen-associated molecular pattern; TIR, Toll-IL-1R; TRIF, TIR domain-containing adaptor inducing IFN-; DC, dendritic cell.

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