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Intestinal mast cell-derived leukotrienes mediate the anaphylactic response to ingested antigens

ABSTRACT: Anaphylaxis is a life-threatening complication of allergen exposure. While mechanisms governing anaphylaxis after intravenous injection have been defined in mice, these models neglect mucosal exposure that accompanies food ingestion. We investigated the role of mast cell populations within the intestine of mice in response to antigens delivered orally. Oral anaphylaxis required IgE-FcεR1 signaling, and profiling of intestinal mast cells revealed a rapidly developing population shaped by epithelial cues. Intestinal mast cells were largely epithelium-resident and displayed divergent transcriptomes and effector functions from connective tissue mast cells found throughout the body. Histamine synthesis was diminished and leukotriene generation enhanced. Mice genetically deficient in cysteinyl leukotriene synthesis, or those treated with aLOX5 antagonist, Zileuton, were protected from oral anaphylaxis whereas that elicited by intravenous injection was unaltered.

ORGANISM(S): Mus musculus

PROVIDER: GSE293904 | GEO | 2025/08/07

REPOSITORIES: GEO

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Project description:Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors This model is described in the article: Systems pharmacology models can be used to understand complex pharmacokinetic-pharmacodynamic behavior: an example using 5-lipoxygenase inhibitors. Demin O, Karelina T, Svetlichniy D, Metelkin E, Speshilov G, Demin O Jr, Fairman D, van der Graaf PH, Agoram BM. CPT Pharmacometrics Syst Pharmacol 2013; 2: e74 Abstract: Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO enzyme, leukotriene signaling and bronchodilation, and the PK of zileuton. The model provided a plausible explanation for the two-phase bronchodilatory effect of zileuton-the short-term bronchodilation was due to leukotriene inhibition and the long-term bronchodilation was due to inflammatory cell infiltration blockade. The model also indicated that the theoretical maximum bronchodilation of both 5LO inhibition and leukotriene receptor blockade is likely similar. QSP modeling provided interesting insights into the effects of leukotriene modulation.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e74; doi:10.1038/psp.2013.49; advance online publication 11 September 2013. This model is hosted on BioModels Database and identified by: BIOMD0000000490. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Intestinal mast cell-derived leukotrienes mediate the anaphylactic response to ingested antigens

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