Osorio-Perez Rubi M, Cruz Silvia L, Gonzalez-Espinosa Claudia
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, CP 14330 Mexico City, Mexico.
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, CP 14330 Mexico City, Mexico.
Int Immunopharmacol. 2025 Jan 27;146:113891. doi: 10.1016/j.intimp.2024.113891. Epub 2024 Dec 27.
Mast cells (MC) are crucial effectors in immediate allergic reactions. Monomeric IgE sensitizes MC and triggers various signaling responses. FcεRI/IgE/antigen crosslinking induces the release of several mediators, including bioactive lipids, but little is known about endocannabinoids (eCBs) secretion. Here, we studied the effects of IgE-induced sensitization and FcεRI crosslinking on anandamide (AEA) synthesis and release in bone marrow-derived mast cells (BMMC). Our results showed that mIgE induced AEA secretion through phospholipase C activation. Secreted AEA contributed to p38 phosphorylation induced by mIgE sensitization. Prolonged mIgE sensitization promoted the formation of long-lasting CB2-GPR55 heteromers. FcεRI crosslinking also caused AEA production. Notably, CB2 deficiency increased IL-2 and IL-3 cytokine expression in response to FcɛRI crosslinking. CB2 and GPR55 agonists reduced IL-2 and IL-3 mRNA expression caused by FcεRI activation. Our findings suggest that a) IgE binding to FcɛRI and its antigen-dependent activation leads to an AEA-dependent autocrine regulatory loop that contributes to intracellular signaling in MC and that b) CB2 and GPR55 receptors play a critical role in modulating the effector phase of MC activation by specifically regulating cytokine expression.
肥大细胞（MC）是速发型过敏反应中的关键效应细胞。单体IgE使MC致敏并触发各种信号反应。FcεRI/IgE/抗原交联诱导多种介质的释放，包括生物活性脂质，但关于内源性大麻素（eCBs）的分泌知之甚少。在此，我们研究了IgE诱导的致敏和FcεRI交联对骨髓来源的肥大细胞（BMMC）中花生四烯酸乙醇胺（AEA）合成和释放的影响。我们的结果表明，膜结合型IgE（mIgE）通过激活磷脂酶C诱导AEA分泌。分泌的AEA促成了mIgE致敏诱导的p38磷酸化。长时间的mIgE致敏促进了持久的CB2-GPR55异源二聚体的形成。FcεRI交联也导致AEA产生。值得注意的是，CB2缺陷会增加FcɛRI交联诱导的白细胞介素-2（IL-2）和白细胞介素-3（IL-3）细胞因子表达。CB2和GPR55激动剂可降低FcεRI激活引起的IL-2和IL-3 mRNA表达。我们的研究结果表明：a）IgE与FcɛRI结合及其抗原依赖性激活导致一个依赖AEA的自分泌调节环，该调节环有助于MC中的细胞内信号传导；b）CB2和GPR55受体通过特异性调节细胞因子表达在调节MC激活的效应阶段中起关键作用。
