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* Department of Molecular and Cellular Interactions and
Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels;
Cell and Tissue Laboratory, Unité de Recherche en Physiologie Moléculaire, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium; and
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
Uncontrolled inflammation is a major cause of tissue injury/pathogenicity often resulting in death of a host infected with African trypanosomes. Thus, comparing the immune response in hosts that develop different degrees of disease severity represents a promising approach to discover processes contributing to trypanosomiasis control. It is known that limitation of pathogenicity requires a transition in the course of infection, from an IFN-
-dependent response resulting in the development of classically activated myeloid cells (M1), to a counterbalancing IL-10-dependent response associated with alternatively activated myeloid cells (M2). Herein, mechanisms and downstream effectors by which M2 contribute to lower the pathogenicity and the associated susceptibility to African trypanosomiasis have been explored. Gene expression analysis in IL-10 knockout and wild-type mice, that are susceptible and relatively resistant to Trypanosoma congolense infection, respectively, revealed a number of IL-10-inducible genes expressed by M2, including Sepp1 coding for selenoprotein P. Functional analyses confirm that selenoprotein P contributes to limit disease severity through anti-oxidant activity. Indeed, Sepp1 knockout mice, but not Sepp1
240-361 mice retaining the anti-oxidant motif but lacking the selenium transporter domain of selenoprotein P, exhibited increased tissue injury that associated with increased production of reactive oxygen species and increased apoptosis in the liver immune cells, reduced parasite clearance capacity of myeloid cells, and decreased survival. These data validate M2-associated molecules as functioning in reducing the impact of parasite infection on the host.
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1 This work, performed in frame of an Interuniversity Attraction Pole Program, was supported by grants from the Institute for Promotion of Innovation by Science and Technology in Flanders and the Fund for Scientific Research Flanders, and by a grant from Institute for Promotion of Innovation by Science and Technology in Flanders for Generisch Basisonderzoek aan de Universiteiten. R.F.B. and K.E.H. are supported by National Institutes of Health Grant ES02497.
2 Address correspondence and reprint requests to Dr. Alain Beschin, Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, Laboratory of Cellular and Molecular Immunology, Pleinlaan 2, 1050 Brussels, Belgium. E-mail address: abeschin{at}vub.ac.be
3 Abbreviations used in this paper: MC, myeloid cell; ROS, reactive oxygen species; Sepp1, selenoprotein P; Sepp1240-361, selenoprotein P truncated of amino acids 240–361; Ctss, cathepsin S; Ngfb, nerve growth factor β; F13a1, coagulation factor XIII, A1 subunit; Treg, T regulatory cell; KO, knockout.
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  M. Guilliams, K. Movahedi, T. Bosschaerts, T. VandenDriessche, M. K. Chuah, M. Herin, A. Acosta-Sanchez, L. Ma, M. Moser, J. A. Van Ginderachter, et al. IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection J. Immunol., January 15, 2009; 182(2): 1107 - 1118. [Abstract] [Full Text] [PDF]
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