Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decreases H. polygyrus adenosine triphosphate content and fecundity. Importantly, RELM-β–driven immunity does not require T or B cells, alternative macrophage activation, or increased gut permeability. Thus, we demonstrate a novel mechanism for host protection at the mucosal interface that explains how stimulation of epithelial cells by IL-4 and IL-13 contributes to protection against parasitic helminthes that dwell in the intestinal lumen.
Alternatively activated macrophages prevent lethal intestinal pathology caused by worm ova in mice infected with the human parasite Schistosoma mansoni through mechanisms that are currently unclear. This study demonstrates that arginase I (Arg I), a major product of IL-4– and IL-13–induced alternatively activated macrophages, prevents cachexia, neutrophilia, and endotoxemia during acute schistosomiasis. Specifically, Arg I-positive macrophages promote TGF-β production and Foxp3 expression, suppress Ag-specific T cell proliferation, and limit Th17 differentiation. S. mansoni-infected Arg I-deficient bone marrow chimeras develop a marked accumulation of worm ova within the ileum but impaired fecal egg excretion compared with infected wild-type bone marrow chimeras. Worm ova accumulation in the intestines of Arg I-deficient bone marrow chimeras was associated with intestinal hemorrhage and production of molecules associated with classical macrophage activation (increased production of IL-6, NO, and IL-12/IL-23p40), but whereas inhibition of NO synthase-2 has marginal effects, IL-12/IL-23p40 neutralization abrogates both cachexia and intestinal inflammation and reduces the number of ova within the gut. Thus, macrophage-derived Arg I protects hosts against excessive tissue injury caused by worm eggs during acute schistosomiasis by suppressing IL-12/IL-23p40 production and maintaining the Treg/Th17 balance within the intestinal mucosa.
Background-Peanut allergy is the most common food-related cause of lethal anaphylaxis and, unlike other food allergies, typically persists into adulthood. Resistance to digestion and dendritic cell activation by the major peanut allergen, Ara h1, are reported to contribute to its allergenicity.
The cytokines IL-10 and TGF-β regulate immunity and inflammation. IL-10 is known to suppress the extent of hepatic damage caused by parasite ova during natural infection with Schistosoma mansoni, but the role of TGF-β is less clear. Cytokine blockade studies in mice revealed that anti-IL-10R mAb treatment during acute infection modestly increased cytokine production and liver damage, whereas selective anti-TGF-β mAb treatment had marginal effects. In contrast, mice administered both mAbs developed severe hepatic inflammation, with enlarged, necrotic liver granulomas, cachexia, and >80% mortality by 8 wk postinfection, despite increased numbers of CD4+CD25+Foxp3+ T regulatory cells. Blocking both IL-10 and TGF-β at the onset of egg production also significantly increased IL-4, IL-6, TNF, IFN-γ, and IL-17 production and markedly increased hepatic, peritoneal, and splenic neutrophilia. In contrast, coadministration of anti-IL-10R and TGF-β mAbs had little effect upon parasite ova-induced intestinal pathology or development of alternatively activated macrophages, which are required to suppress intestinal pathology. This suggests that inflammation is controlled during acute S. mansoni infection by two distinct, organ-specific mechanisms: TGF-β and IL-10 redundantly suppress hepatic inflammation while intestinal inflammation is regulated by alternatively activated macrophages.
Rationale
Intestinal anaphylaxis (manifested by acute diarrhea) is dependent on IgE and mast cells.
Objective
We aimed to define the respective roles of IL-4 and IL-13 and their receptors in disease pathogenesis.
Methods
Wild-type mice and mice deficient in IL-4, IL-13, and IL-13Rα1 (part of the type 2 IL-4R) were sensitized with ovalbumin (OVA)/alum and subsequently given repeated intragastric OVA exposures. IL-4Rα chain was targeted with anti-IL-4Rα mAb prior to or after intragastric OVA exposures.
Results
IL-4−/− (and IL-4/13−/−) mice produced almost no IgE and were highly resistant to OVA-induced diarrhea, whereas allergic diarrhea was only partially impaired in IL-13−/− and IL-13Rα1−/− mice. IL-13Rα1-deficient mice developed decreased IgE despite having normal baseline IL-4 levels. Intestinal mast cell accumulation and activation also depended mainly on IL-4 and to a lesser extent on IL-13. Prophylactic anti-IL-4Rα mAb treatment, which blocks all IL-4 and IL-13 signaling, suppressed development of allergic diarrhea. However, treatment with anti-IL-4Rα mAb for 7 days only partially suppressed IgE and did not prevent intestinal diarrhea.
Conclusion
Endogenously-produced IL-13 supplements the ability of IL-4 to induce allergic diarrhea by promoting oral allergen sensitization rather than the effector phase of intestinal anaphylaxis.
IL 4 receptor α (IL-4Rα) expression by non-bone marrow (BM)-derived cells is required to protect hosts against several parasitic helminth species. In contrast, we demonstrate that IL-4Rα 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-4Rα expression by non-BM-derived cells is neither necessary nor sufficient. Chimeras that express IL-4Rα only on non-BM-derived cells still produce Th2 cytokines, but overproduce IL-12p40, TNF, and IFN-γ, fail to generate alternatively activated macrophages, and develop endotoxemia and severe hepatic and intestinal pathology. In contrast, chimeras that express IL-4Rα 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-4Rα-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.
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