Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice

• 成果类型: Article
• 署名作者: Hoyt, Laura R.; Liu, Elise; Olson, Eli C.; Jacobsen, Danielle R.; Siniscalco, Emily R.; Krier-Burris, Rebecca A.; Greenfield, Kara G.; Mcbride, Caleb D.; Alfajaro, Mia M.; Amat, Julien A. R.; Zhao, Zhe; Xu, Lan; Philip, Vivek; Verma, Aditi; Fourati, Slim; Senger, Donna L.; Zhang, Lingdi; Bunyavanich, Supinda; Glass, Sarah E.; Coffey, Robert J.; Wilen, Craig B.; Williams, Adam; Eisenbarth, Stephanie C.
• 署名单位: Yale University; Yale University; Yale University; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Jackson Laboratory; Jewish General Hospital - Montreal; Lady Davis Institute; McGill University; Icahn School of Medicine at Mount Sinai; Vanderbilt University; Vanderbilt University; Vanderbilt University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11118
• DOI: 10.1126/science.adp0240
• 发表日期: 2025-08-07
• 关键词: oral sensitization; mast-cells; intestinal permeability; membrane dipeptidase; epithelial-cells; murine model; peanut; antigen; ige; proteins

摘要

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.