Bachtel Nathaniel D, Cullen Jaime L, Liu Min, Erickson Steven A, Kutyavin Vassily I, El-Naccache Darine W, Florsheim Esther B, Lim Jaechul, Sullivan Zuri A, Imaeda Raiden, Hudak Andrew, Zhang Cuiling, Medzhitov Ruslan
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
School of Life Sciences, Arizona State University, Tempe, AZ, USA.
Science. 2025 Aug 7;389(6760):eadp0246. doi: 10.1126/science.adp0246.
Anaphylaxis is a life-threatening complication of food allergen exposure. Although mechanisms governing anaphylaxis after intravenous injection are defined in mice, these models neglect mucosal exposure that accompanies ingestion. We investigated the role of mast cells within the intestine of mice and found that oral anaphylaxis required immunoglobulin E-Fcε receptor 1 (IgE-FcεR1) signaling. Intestinal mast cells were a heterogeneous population, shaped by epithelial cues. Compared with connective tissue mast cells found throughout the body, intestinal mast cells largely resided in the epithelium, displayed divergent transcriptomes and effector functions, and had a diminished ability to generate histamine, but they enhanced leukotriene synthesis. Mice genetically deficient in cysteinyl leukotriene synthesis, or those treated with the arachidonate 5-lipoxygenase (aLOX5) antagonist zileuton, were protected from oral antigen-induced responses, whereas those elicited by intravenous injection were unaltered.
过敏反应是食物过敏原暴露引发的危及生命的并发症。虽然小鼠静脉注射后过敏反应的机制已明确，但这些模型忽略了摄入时伴随的黏膜暴露。我们研究了小鼠肠道内肥大细胞的作用，发现口服过敏反应需要免疫球蛋白E - Fcε受体1（IgE - FcεR1）信号传导。肠道肥大细胞是一个异质性群体，由上皮信号塑造。与全身各处的结缔组织肥大细胞相比，肠道肥大细胞主要位于上皮内，表现出不同的转录组和效应功能，产生组胺的能力减弱，但增强了白三烯的合成。半胱氨酰白三烯合成基因缺陷的小鼠，或用花生四烯酸5 - 脂氧合酶（aLOX5）拮抗剂齐留通治疗的小鼠，可免受口服抗原诱导的反应影响，而静脉注射引发的反应则不受影响。
