title: IFN-γ-driven IDO production from macrophages protects IL-4Rα-deficient mice against lethality during Schistosoma mansoni infection.
abstract: The balance between alternatively activated macrophages (AAMs)/M2 cells and classically activated macrophages (M1 cells) is largely dependent on the effects of IL-4 and interferon (IFN)-γ, respectively. Although AAM/M2 cells can suppress inflammation and repair damaged tissue, M1 cells produce an array of pro-inflammatory molecules. Macrophage effector functions are critical for host protection against many infectious diseases, but it remains unknown whether lethal immunopathological characteristics, caused by Schistosoma mansoni infection in IL-4 receptor α-deficient mice (IL-4Rα(-/-)), results from the absence of M2 cells or increased numbers of M1 cells. In this study, we generated mice that completely lack IL-4Rα signaling in the context of a macrophage-specific loss of IFN-γ responsiveness (MIIG × IL-4Rα(-/-)). Contrary to what we expected, acute schistosomiasis resulted in greater liver injury and mortality in MIIG × IL-4Rα(-/-) mice compared with IL-4Rα(-/-) mice. Greater tissue injury in MIIG × IL-4Rα(-/-) mice was likely because of a lack of indoleamine 2,3 dioxygenase (IDO), a critical regulator of immunosuppression. Indeed, MIIG × IL-4Rα(-/-) failed to up-regulate IDO expression, and IL-4Rα(-/-) mice treated with an IDO antagonist underwent greater liver damage and mortality compared with mock-treated IL-4Rα(-/-) mice. Thus, we propose that, in the absence of AAM/M2 cells, IFN-γ-induced M1 cells suppress tissue-damaging inflammation during acute schistosomiasis through an IDO-dependent mechanism.
authors.affiliation: Division of Cellular and Molecular Immunology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Rani
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.forename: De'Broski R
authors.initials: DR
authors.lastname: Herbert
mesh_terms: D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008099:Liver / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019948:Receptors, Interleukin-4 / Q000172:deficiency* / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000201:enzymology / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016019:Survival Analysis; D015431:Weight Loss / Q000276:immunology
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D007371:Interferon-gamma