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IL-4R Expression by Bone Marrow-Derived Cells Is Necessary and Sufficient for Host Protection against Acute Schistosomiasis¹

De’Broski R. Herbert^*,, Tatyana Orekov^*,, Charles Perkins^*,, Marc E. Rothenberg and Fred D. Finkelman^2,*,,

^* Research Service (151), Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220; Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; and Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229

IL 4 receptor (IL-4R) expression by non-bone marrow (BM)-derived cells is required to protect hosts against several parasitic helminth species. In contrast, we demonstrate that IL-4R expression by BM-derived cells is both necessary and sufficient to prevent Schistosoma mansoni-infected mice from developing severe inflammation directed against parasite ova, whereas IL-4R expression by non-BM-derived cells is neither necessary nor sufficient. Chimeras that express IL-4R only on non-BM-derived cells still produce Th2 cytokines, but overproduce IL-12p40, TNF, and IFN-, fail to generate alternatively activated macrophages, and develop endotoxemia and severe hepatic and intestinal pathology. In contrast, chimeras that express IL-4R only on BM-derived cells have extended survival, even though the granulomas that they develop around parasite eggs are small and devoid of collagen. These observations identify distinct roles for IL-4/IL-13 responsive cell lineages during schistosomiasis: IL-4R-mediated signaling in non-BM-derived cells regulates granuloma size and fibrosis, whereas signaling in BM-derived cells suppresses parasite egg-driven inflammation within the liver and intestine.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the U.S. Department of Veterans Affairs and National Institutes of Health Grants R01 GM49758 and R01 AI052099, which included a diversity supplement.

² Address correspondence and reprint requests to Dr. Fred D. Finkelman, Research Service (151), Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220. E-mail address: ffinkelman{at}pol.net

³ Abbreviations used in this paper: IL-4R, IL-4 receptor -chain; BM, bone marrow; M, macrophage; AAM, alternatively activated macrophage; CAM, classically activated macrophage; NOS-2, inducible NO synthase; WT, wild type; FIZZ-1, relm-; AST, aspartate transaminase.

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