Hung, L.Y. et al. IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms. Proc. Natl. Acad. Sci. USA 110, 282-287

Division of Experimental Medicine, University of California, San Francisco, CA 94110.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2012; 110(1). DOI: 10.1073/pnas.1206587110
Source: PubMed

ABSTRACT Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4(+) T helper 2 cells (T(H)2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33-deficient mice have a selective defect in ILC2-derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4(+) T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33-deficient mice impairs resistin-like molecule beta (RELMβ) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4-driven Type 2 responses during hookworm infection.

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Available from: De'Broski R Herbert, Aug 22, 2015
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    • "In this same study, IL-33 deficiency led to greater hemorrhaging at day 3 post infection, along with reduced eosinophil recruitment to the lung. Thus IL-33 is critical for worm expulsion, while also minimizing host damage early in infection [30] "
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    ABSTRACT: Metazoan parasites typically induce a type 2 immune response, characterized by T helper 2 (Th2) cells that produce the cytokines IL-4, IL-5 and IL-13 among others. The type 2 response is host protective, reducing the number of parasites either through direct killing in the tissues, or expulsion from the intestine. Type 2 immunity also protects the host against damage mediated by these large extracellular parasites as they migrate through the body. At the center of both the innate and adaptive type 2 immune response, is the IL-4Rα that mediates many of the key effector functions. Here we highlight the striking overlap between the molecules, cells and pathways that mediate both parasite control and tissue repair. We have proposed that adaptive Th2 immunity evolved out of our innate repair pathways to mediate both accelerated repair and parasite control in the face of continual assault from multicellular pathogens. Type 2 cytokines are involved in many aspects of mammalian physiology independent of helminth infection. Therefore understanding the evolutionary relationship between helminth killing and tissue repair should provide new insight into immune mechanisms of tissue protection in the face of physical injury.
    Seminars in Immunology 08/2014; 26(4). DOI:10.1016/j.smim.2014.06.003 · 6.12 Impact Factor
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    • "Increases in type 2 cytokines (Figure 4F) and M2 markers (Figure 4G) were largely inhibited after primary Hp inoculation of A 2B AR À/À mice compared to inoculated WT mice. Previous studies have indicated that IL-33 may drive the development of both innate and adaptive type 2 immune responses (Hung et al., 2013). "
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    ABSTRACT: The type 2 immune response evoked by intestinal nematode parasites contributes to worm expulsion and tolerance to associated tissue damage. We investigated whether this host response is affected by blocking signaling by the putative endogenous danger signal adenosine, which can be released during inflammation and host cell damage. Specific blockade of the A2B adenosine receptor (A2BAR) inhibited worm elimination and the development of innate and adaptive components of the type 2 primary and memory response. Infected mice lacking A2BAR exhibited decreased M2 macrophage and eosinophil recruitment and reduced IL-4 and IL-13 cytokine production. Additionally, shortly after infection, upregulation of the alarmin IL-33, which drives type 2 immunity, and activation of innate lymphoid type 2 (ILC2) cells was inhibited, while exogenous IL-33 restored ILC2 cell activation and type 2 cytokine expression. Thus, adenosine acts as a danger-associated molecular pattern (DAMP) that initiates helminth-induced type 2 immune responses through A2BAR.
    Cell host & microbe 03/2014; 15(3):339-50. DOI:10.1016/j.chom.2014.02.001 · 12.19 Impact Factor
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    • "In addition, induction of nuocytes and ih2 cells can be achieved in the presence of IL-33 (Neill et al., 2010; Price et al., 2010), but this cytokine is not required to mount a protective response against N. brasiliensis (Senn et al., 2000). Moreover, recent studies indicate that IL-33 can drive CD4-mediated IL-13 production in the N. brasiliensis infection model although the majority of the effect is at the level of IL-33 induced ILC2 producing IL-13 in the gut environment leading to worm expulsion (Hung et al., 2012). An interesting set of studies recently resurrected the issue that innate cells able to produce IL-4 could play a role in Th2 differentiation (Le Gros et al., 1990). "
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    ABSTRACT: Of all the microbial infections relevant to mammals the relationship between parasitic worms and what constitutes and regulates a host protective immune response is perhaps the most complex and evolved. Nippostrongylus brasiliensis is a tissue migrating parasitic roundworm of rodents that exemplifies many of the salient features of parasitic worm infection, including parasite development through sequential larval stages as it migrates through specific tissue sites. Immune competent hosts respond to infection by N. brasiliensis with a rapid and selective development of a profound Th2 immune response that appears able to confer life long protective immunity against reinfection. This review details how the lung can be the site of migrating nematode immune killing and the gut a site of rapid immune mediated clearance of worms. Furthermore it appears that N. brasiliensis induced responses in the lung are sufficient for conferring immunity in lung and gut while infection of the gut only confers immunity in the gut. This review also covers the role of IL-4, STAT6, and the innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin in the generation of CD4-mediated immunity against N. brasiliensis reinfection and discusses what cytokines might be involved in mediated killing or expulsion of helminth parasites.
    Frontiers in Immunology 03/2013; 4:74. DOI:10.3389/fimmu.2013.00074
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