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Am J Pathol. 2012 May;180(5):2001-8. doi: 10.1016/j.ajpath.2012.01.013. Epub 2012 Mar 16.

IFN-γ-driven IDO production from macrophages protects IL-4Rα-deficient mice against lethality during Schistosoma mansoni infection.

Author information

1
Division of Cellular and Molecular Immunology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA.

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.

PMID:
22426339
PMCID:
PMC3349826
DOI:
10.1016/j.ajpath.2012.01.013
[Indexed for MEDLINE]
Free PMC Article

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