IL-13 attenuates gastrointestinal candidiasis in normal and immunodeficient RAG-2(-/-) mice via peroxisome proliferator-activated receptor-gamma activation.
We recently demonstrated that in vitro peroxisome proliferator-activated receptor-gamma (PPARgamma) activation of mouse peritoneal macrophages by IL-13 or PPARgamma 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 PPARgamma-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 PPARgamma antagonist, and are reduced in PPARgamma(+/-) mice. Overall, these data demonstrate that IL-13 or PPARgamma ligands attenuate C. albicans infection of the GI tract through PPARgamma activation and hence suggest that PPARgamma ligands may be of therapeutic value in esophageal and GI candidiasis in immunocompromised patients.
Coste
Agnès
A
Laboratoire Polarisation des Macrophages and Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Paul Sabatier Toulouse III, INSERM, Institut Fédératif de Recherche 31, Institut Louis Bugnard, Toulouse, France.
Lagane
Céline
C
Filipe
Cédric
C
Authier
Hélène
H
Galès
Amandine
A
Bernad
José
J
Douin-Echinard
Victorine
V
Lepert
Jean-Claude
JC
Balard
Patricia
P
Linas
Marie-Denise
MD
Arnal
Jean-François
JF
Auwerx
Johan
J
Pipy
Bernard
B
D000818:Animals; D002176:Candida albicans / Q000187:drug effects / Q000502:physiology; D002177:Candidiasis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002432:Cecum / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005767:Gastrointestinal Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018793:Interleukin-13 / Q000627:therapeutic use*; D037181:Lectins, C-Type / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
D004268:DNA-Binding Proteins; D018793:Interleukin-13; D037181:Lectins, C-Type; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D047495:PPAR gamma; C499308:Rag2 protein, mouse; D011956:Receptors, Cell Surface; D045162:Thiazolidinediones; D000077154:Rosiglitazone