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IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2^–/– Mice via Peroxisome Proliferator-Activated Receptor- Activation¹

Agnès Coste^2,*,, Céline Lagane^2,*, Cédric Filipe, Hélène Authier^*, Amandine Galès^*, José Bernad^*, Victorine Douin-Echinard, Jean-Claude Lepert^*, Patricia Balard^*, Marie-Denise Linas^*,, Jean-François Arnal, Johan Auwerx and Bernard Pipy^3,*

^* Laboratoire Polarisation des Macrophages and Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Paul Sabatier Toulouse III, Institut National de la Santé et de la Recherche Médicale (INSERM) Institut Fédératif de Recherche (IFR) 31, Institut Louis Bugnard, Toulouse, France; Institut de Génétique et Biologie Moléculaire et Cellulaire, INSERM/Centre National de la Recherche Scientifique, Illkirch, France; Département de Parasitologie et Mycologie, Centre Hospitalier Universitaire, Hôpital Rangueil, Toulouse, France; and INSERM Unité 858, IFR31, Institut Louis Bugnard, Toulouse, France

We recently demonstrated that in vitro peroxisome proliferator-activated receptor- (PPAR) activation of mouse peritoneal macrophages by IL-13 or PPAR ligands promotes uptake and killing of Candida albicans through mannose receptor overexpression. In this study, we demonstrate that i.p. treatment of immunocompetent and immunodeficient (RAG-2^–/–) mice with natural and synthetic PPAR-specific ligands or with IL-13 decreases C. albicans colonization of the gastrointestinal (GI) tract 8 days following oral infection with the yeast. We also showed that Candida GI infection triggers macrophage recruitment in cecum mucosa. These mucosal macrophages, as well as peritoneal macrophages, overexpress the mannose receptor after IL-13 and rosiglitazone treatments. The treatments promote macrophage activation against C. albicans as suggested by the increased ability of peritoneal macrophages to phagocyte C. albicans and to produce reactive oxygen intermediates after yeast challenge. These effects on C. albicans GI infection and on macrophage activation are suppressed by treatment of mice with GW9662, a selective PPAR antagonist, and are reduced in PPAR^+/– mice. Overall, these data demonstrate that IL-13 or PPAR ligands attenuate C. albicans infection of the GI tract through PPAR activation and hence suggest that PPAR ligands may be of therapeutic value in esophageal and GI candidiasis in immunocompromised patients.

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 A.C. was supported by SIDACTION, C.L. by the French Ministry of Education, Research and Technology. This work was also supported by a grant from the Tarn et Garonne Committee of the Ligue Contre le Cancer.

² C.L. and A.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Bernard Pipy, Laboratoire Polarisation des Macrophages and Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Paul Sabatier Toulouse III, INSERM IFR31, Institut Louis Bugnard, BP 84225, 31432 Toulouse cedex 4, France. E-mail address: Pipy{at}toulouse.inserm.fr

⁴ Abbreviations used in this paper: GI, gastrointestinal; ROI, reactive oxygen intermediate; MR, mannose receptor; PPAR, peroxisome proliferator-activated receptor-; SDA, Sabouraud dextrose agar; CL, chemiluminescence; mBSA, mannosylated BSA; LXR-, liver X receptor-.

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