IFN-γ-Driven IDO Production from Macrophages Protects IL-4Rα-Deficient Mice against Lethality during Schistosoma mansoni Infection

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)-gamma, 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 alpha-deficient mice (IL4-R alpha(-/-)) results from the absence of M2 cells or increased numbers of M1 cells. In this study, we generated mice that completely lack IL-4R alpha signaling in the context of a macrophage-specific loss of IFN-gamma responsiveness (MIIG x IL-4R alpha(-/-)). Contrary to what we expected, acute schistosomiasis resulted in greater liver injury and mortality in MIIG x IL-4R alpha(-/-) mice compared with IL-4R alpha(-/-) mice. Greater tissue injury in WIIG x IL-4R alpha(-/-) mice was likely because of a lack of indoleamine 2,3 dioxygenase (IDO), a critical regulator of immunosuppression. Indeed, MIIG x IL-4R alpha(-/-) failed to upregulate IDO expression, and IL-4R alpha(-/-) mice treated with an IDO antagonist underwent greater liver damage and mortality compared with mock-treated IL-4R alpha(-/-) mice. Thus, we propose that, in the absence of AAM/M2 cells, IFN-gamma-induced M1 cells suppress tissue-damaging Inflammation during acute schistosomiasis through an IDO-dependent mechanism. (Am J Pathol 2012, 180: 2001-2008; DOI: 10.1016/j.ajpath.2012.01.013)