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Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy.

ABSTRACT: Interleukin (IL)-4 has critical roles in allergic disorders, including food hypersensitivity. The direct effects of the cytokine on the survival and function of mast cells, the key effectors of food anaphylaxis, have not been established. In this study, we demonstrate that IL-4 induces a marked intestinal mastocytosis in mice. This phenotype is reproduced in animals expressing Il4r?F709, an activating variant of the IL-4 receptor ?-chain (IL-4R?). Il4r?F709 mice exhibit enhanced anaphylactic reactions but unaltered physiological responses to vasoactive mediators. IL-4 induces Bcl-2 and Bcl-X(L) and enhances survival and stimulates proliferation in cultured bone marrow-derived mast cells (BMMC). These effects are STAT6 (signal transducer and activator of transcription factor 6)-dependent and are amplified in Il4r?F709 BMMC. In competitive bone marrow chimeras, Il4r?F709 mast cells display a substantial competitive advantage over wild-type mast cells, which, in turn, prevail over IL-4R??/? mast cells in populating the intestine, establishing a cell-intrinsic effect of IL-4 in intestinal mast cell homeostasis. Our results demonstrate that IL-4-signaling is a key determinant of mast cell expansion in food allergy.

SUBMITTER: Burton OT

PROVIDER: S-EPMC3600405 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy.

Burton O T OT Darling A R AR Zhou J S JS Noval-Rivas M M Jones T G TG Gurish M F MF Chatila T A TA Oettgen H C HC

Mucosal immunology 20121114 4

Interleukin (IL)-4 has critical roles in allergic disorders, including food hypersensitivity. The direct effects of the cytokine on the survival and function of mast cells, the key effectors of food anaphylaxis, have not been established. In this study, we demonstrate that IL-4 induces a marked intestinal mastocytosis in mice. This phenotype is reproduced in animals expressing Il4rαF709, an activating variant of the IL-4 receptor α-chain (IL-4Rα). Il4rαF709 mice exhibit enhanced anaphylactic rea ...[more]

PMID: 23149659

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Project description:There is heterogeneity inherent in the immune responses of individual mice in murine models of food allergy, including anaphylaxis, similar to the clinical heterogeneity observed in humans with food allergies to a defined food. One major driver of this heterogeneity may be differences in the microbiome between sensitized individuals. Our laboratory and others have reported that disruption of the microbiome (dysbiosis) by broad spectrum antibiotics and/or yeast colonization can alter systemic immunity and favor the development of mucosal Type 2 immunity to aeroallergens. Our objective was to use a well-characterized murine model (Balb/c mice) of food allergies (chicken egg ovalbumin, OVA) and determine if antibiotic-mediated dysbiosis (including C. albicans colonization) could enhance the manifestation of food allergies. Furthermore, we sought to identify elements of the microbiome and host response that were associated with this heterogeneity in the anaphylactic reaction between individual food allergen-sensitized mice. In our dataset, the intensity of the anaphylactic reactions was most strongly associated with a disrupted microbiome that included colonization by C. albicans, loss of a specific Lachnoclostridium species (tentatively, Lachnoclostridium YL32), development of a highly polarized Type 2 response in the intestinal mucosa and underlying tissue, and activation of mucosal mast cells. Serum levels of allergen-specific IgE were not predictive of the response and a complete absence of a microbiome did not fully recapitulate the response. Conventionalization of germ-free mice resulted in Akkermansia muciniphila outgrowth and a higher degree of heterogeneity in the allergic response. C57BL/6 mice remained resistant even under the same dysbiosis-inducing antibiotic regimens, while changes in the microbiome markedly altered the reactivity of Balb/c mice to OVA, as noted above. Strikingly, we also observed that genetically identical mice from different rooms in our vivarium develop different levels of a Type 2 response, as well as anaphylactic reactions. The intestinal microbiome in these mice also differed between rooms. Thus, our data recapitulate the heterogeneity in anaphylactic reactions, ranging from severe to none, seen in patients that have circulating levels of food allergen-reactive IgE and support the concept that alterations in the microbiome can be one factor underlying this heterogeneity.

Dataset Information

Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy.

Publications

Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy.

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