2025-08-07 ノースウェスタン大学
<関連情報>
- https://news.northwestern.edu/stories/2025/08/asthma-drug-zileuton-blocks-food-allergy-reactions-in-mice/
- https://www.science.org/doi/10.1126/science.adp0240
システイン型ロイコトリエンはマウスにおいて食物アレルゲンの腸管吸収を促進し、アナフィラキシーを引き起こす Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice
Laura R. Hoyt, Elise Liu, Eli C. Olson, Danielle R. Jacobsen, […] , and Stephanie C. Eisenbarth
Science Published:7 Aug 2025
DOI:https://doi.org/10.1126/science.adp0240
Editor’s summary
Cysteinyl leukotrienes (CysLTs) are inflammatory mediators implicated in allergic responses, particularly asthma. Two studies examined the role of CysLTs in the development of anaphylaxis in response to ingested food allergens in mice. Hoyt et al. found that CysLTs promoted the transport of intact food allergens from the gut lumen into the tissue. Mice that did not experience anaphylaxis had variants of DPEP1, an enzyme that metabolizes CysLTs, linked to augmented enzymatic activity. Batchel et al. found that when cells from the hematopoietic compartment could not synthesize CysLTs, mice had attenuated responses to ingested allergens. Mast cells within the intestinal epithelium could synthesize and respond to CysLTs. In both studies, blocking the synthesis of CysLTs using the drug zileuton before or concurrent with food-allergen exposure prevented the symptoms associated with anaphylaxis in mice (see the Perspective by Haque and Kaplan). —Sarah H. Ross
Structured Abstract
INTRODUCTION
Allergic reactions to food are mediated by cross-linking of preformed food-specific immunoglobulin E (IgE) antibodies bound to tissue mast cells upon allergen exposure. However, some people who have food-specific IgE do not have any allergic reaction to that food and are considered “sensitized tolerant.” How this population remains unresponsive to allergens is unclear, but understanding the underlying mechanisms could identify approaches for treating food allergy.
RATIONALE
To identify the genetic causes of a sensitized tolerant state, we studied an unexplained aspect of food allergy in mouse models. With rare exceptions, the commonly used C57BL/6 mouse strain demonstrates anaphylaxis to food allergens when challenged systemically, but not orally, despite robust IgE production, thus potentially modeling a sensitized tolerant state. The intestinal epithelium is composed of tight junctions that allow ions and small molecules to pass through paracellular transport. Proteins are primarily absorbed as amino acids or small polypeptides that are unable to cross-link IgE, which recognize whole epitopes. Therefore, anaphylaxis can only occur when submucosal mast cells encounter minimally digested food allergens; delivery of intact allergens has been shown to occur by transcellular transport through intestinal secretory cells. We thus hypothesized that transcellular allergen transport is genetically regulated and thereby susceptibility to anaphylaxis.
RESULTS
We found that oral anaphylaxis–resistant C57BL/6 mice have gut barriers that are impermeable to intact food allergens relative to susceptible strains such as C3H/HeJ even before allergic sensitization. Resistance correlated with reduced transport of allergens through secretory cells of the small intestine. Using a forward genetic screen of oral anaphylaxis, we identified a resistance gene, dipeptidase 1 (Dpep1), which encodes an enzyme expressed in the intestinal epithelium that catabolizes a cysteinyl leukotriene (CysLT) lipid inflammatory molecule. Although CysLTs are important mediators of allergic responses, a mechanistic connection between CysLTs and food allergen transport is unknown. We found that oral anaphylaxis–susceptible mice had elevated CysLTs in the gut, suggesting impaired DPEP1 enzymatic activity. Indeed, blockade of DPEP1 with cilastatin enhanced allergen absorption in anaphylaxis-resistant mice. Conversely, inhibition of leukotriene synthesis with zileuton reduced allergen absorption and prevented anaphylaxis after oral challenge in susceptible mice.
CONCLUSION
We discovered a mechanism by which CysLTs promote allergen absorption in the gut, thus increasing susceptibility to anaphylaxis after allergen ingestion. This function was distinct from their classical role in mediating anaphylaxis symptoms. Although multiple genetic and environmental factors likely modulate anaphylaxis, our data implicate DPEP1 as one modulator of intestinal allergen absorption in mice. Our work indicates that the intestinal barrier can protect sensitized individuals from experiencing allergic symptoms upon food ingestion, which could be achieved by reducing gut CysLTs with zileuton. This suggests that blocking leukotriene synthesis could be a treatment for food allergies. Moreover, our investigations have advanced the understanding of what regulates oral anaphylaxis in mouse models, paving the way for physiological allergen exposures to be modeled in C57BL/6 genetically modified mice.
Tuning food allergen transport by gut epithelial cells to trigger anaphylaxis.
Reduced DPEP1 activity causes leukotriene (LTC4 and LTD4) accumulation in the gut, acting on the CysLT receptors 1 and 2 (CysLTR1 and CysLTR2). This promotes food allergen transport through goblet cells to the submucosa and bloodstream, where IgE-loaded mast cells are activated to trigger anaphylaxis. [Figure created with BioRender.com]
Abstract
Food-specific immunoglobulin E (IgE) triggers life-threatening anaphylaxis; however, for unclear reasons, some people with food-specific IgE are asymptomatic upon allergen consumption. We studied strains of mice with different sensitivities to anaphylaxis when orally challenged with allergen to identify possible causes. In resistant C57BL/6 mice, intestinal goblet cells transported less food allergen than did anaphylaxis-susceptible strains, even before allergic sensitization. In a forward genetic screen, resistance was correlated with dipeptidase 1 (Dpep1) variants. DPEP1 is expressed in intestinal epithelium and catabolizes leukotriene D4 (LTD4). Blocking DPEP1 with cilastatin, deleting Dpep1, or administering LTD4 orally enhanced allergen transport in resistant mice. Conversely, pretreatment of susceptible mice with a synthesis inhibitor, zileuton, abrogated allergen absorption and oral anaphylaxis, indicating that this could be an approach to treating food allergy.
