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. 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

Reena Rani  1 , Michael B Jordan, Senad Divanovic, De'Broski R Herbert
Affiliations

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

Reena Rani et al. Am J Pathol. 2012 May.

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.

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Figures

Figure 1
Figure 1
Generation of mice with a macrophage-specific loss of IFN-γ responsiveness and a global loss of IL-4/IL-13 responsiveness. A: Nitrite production from WT, IL-4Rα−/−, or MIIG × IL-4Rα−/− bone marrow–derived macrophages (BMDMs) that were either left untreated (Med) or stimulated with Escherichia coli LPS, 100 ng/mL, or a combination of LPS and IFN-γ, 20 ng/mL, for 24 hours. Data show the mean ± SE of triplicate wells. The experiment was performed three times. **P < 0.001. Flow cytometric analysis of thioglycollate-elicited peritoneal exudate cells from IL-4Rα−/− or MIIG × IL-4Rα−/− mice cell surface expression of Myc (alias c-myc) on CD11b+ and F4/80+ cell populations (B) and CD11b+ and/or Ly6C/G+ cell populations (C). This is representative of three independent mice analyzed per group.
Figure 2
Figure 2
MIIG × IL-4Rα−/− mice develop accelerated weight loss and increased mortality relative to mice that lack IL-4/IL-13 responsiveness on all cells. A: Percentage weight change in WT, MIIG, IL-4Rα−/−, or MIIG × IL-4Rα−/− mice after infection of mice with 50 to 60 S. mansoni cercariae. Data show the mean ± SE (n = 6 to 8 mice per group). The experiment was performed four times. B: Percentage survival from a representative experiment described in A. *P < 0.05, **P < 0.01, and ***P < 0.001 as determined by one-way analysis of variance.
Figure 3
Figure 3
MIIG × IL-4Rα−/− mice show greater liver injury and granulomatous pathological characteristics compared with IL-4Rα−/− mice during acute schistosomiasis. The S. mansoni–infected WT, IL-4Rα−/−, and MIIG × IL-4Rα−/− mice were evaluated at 7.5 weeks after infection for serum levels of AST (A) and liver granuloma cross-sectional area (B). Data show the mean ± SE (n = 300 granulomas per group). C: Representative images of liver granulomas after H&E staining of infected liver tissue at 7.5 weeks after infection. Photomicrographs show representative liver sections from S. mansoni–inoculated mice at 7.5 weeks after infection. Scale bar = 100 μm. Arrows, parasite ova; arrowheads, areas of perivascular inflammation. *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 4
Figure 4
The S. mansoni–infected MIIG × IL-4Rα−/− mice and IL-4Rα−/− mice generate a similar cytokine response within lymphoid and hepatic tissues during the acute infection phase. Supernatant levels of IFN-γ (A), IL-17A (B), IL-5 (C), and IL-12p40 (D), produced from mesenteric lymph node cells of S. mansoni–infected mice at 7 weeks after infection, that were either left untreated (Med) or stimulated with 10 μg/mL SEA, as determined by ELISA. Data show the mean ± SE of triplicate wells (n = 4 mice per group). The experiment was performed three times. Hepatic mRNA expression levels of IL-10 (E) and TGF-β1 (F) were quantified in WT (circles), IL-4Rα−/− (squares), and MIIG × IL-4Rα−/− (triangles) mice at 7 weeks after infection. Open symbols, naïve; closed symbols, infected. The experiment was performed three times. **P < 0.01 as determined by one-way analysis of variance.
Figure 5
Figure 5
The S. mansoni–infected MIIG × IL-4Rα−/− mice fail to up-regulate IDO, which protects IL-4Rα−/− mice against lethal multiorgan inflammation during acute schistosomiasis. Liver (A) and intestinal (B) mRNA expression levels for IDO at 7.5 weeks after infection. Data show the mean ± SE (n = 4 to 6 mice per group). Open symbols, naïve; closed symbols, infected. The experiment was performed twice. C: Percentage weight change in WT and IL-4Rα−/− mice treated with an IDO antagonist (1-MT) or left untreated. D: Percentage survival from the experiment described in C. Data show the mean ± SE (n = 6 to 8 mice per group). The experiment was repeated twice. AST (E) and endotoxin (F) levels in the serum samples of naïve and S. mansoni–infected WT and IL-4Rα−/− mice treated as described in C. Data show the mean ± SE (n = 6 to 8 mice per group). The experiment was performed twice. *P < 0.05 and **P < 0.01 as determined by one-way analysis of variance.
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