Department of Medicine, Harvard Medical School, Boston, Mass; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Mass.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Mass.
J Allergy Clin Immunol. 2019 Mar;143(3):1047-1057.e8. doi: 10.1016/j.jaci.2018.06.033. Epub 2018 Jul 12.
Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C, prostaglandin [PG] D, and thromboxane A), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms.
We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity.
We used an ex vivo model of mouse bone marrow-derived mast cells and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease (AERD).
IL-33 potently liberates AA and elicits LTC, PGD, and thromboxane A production by bone marrow-derived mast cells. Unexpectedly, the constitutive function of COX-1 is required for IL-33 to activate group IVa cytosolic phospholipase A with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX-1 was dispensable for FcεRI-driven CysLT production. Inhibition of COX-1 prevented IL-33-induced phosphorylation of extracellular signal-related kinase, an upstream effector of cytosolic phospholipase A, which was restored by exogenous PGH, implying that the effects of COX-1 required its catalytic function. Administration of a COX-1-selective antagonist to mice completely prevented the generation of both PGD and LTC in a model of AERD in which MC activation is IL-33 driven.
MC-intrinsic COX-1 amplifies IL-33-induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD.
经典 FcεRI 诱导的肥大细胞 (MC) 激活导致花生四烯酸 (AA) 衍生的类二十烷酸 (LT C、PGD 和血栓烷 A) 的合成，这些物质介导血管渗漏、支气管收缩和效应细胞趋化性。对于非经典 MC 激活机制引起的类二十烷酸生成的意义和调节知之甚少。
我们试图确定 MC 衍生的类二十烷酸的调节和意义，这些类二十烷酸是对细胞因子 IL-33 的反应产生的，IL-33 对先天 2 型免疫至关重要。
我们使用了一种体外模型的小鼠骨髓来源的肥大细胞和一种依赖于 IL-33 的阿司匹林加重的呼吸道疾病 (AERD) 的体内模型。
IL-33 强力释放 AA，并引发骨髓来源的肥大细胞产生 LTC、PGD 和血栓烷 A。出乎意料的是，COX-1 的组成性功能对于 IL-33 激活组 IVa 胞质型磷脂酶 A 以随后释放 AA 用于合成所有类二十烷酸，包括 CysLTs 是必需的。相比之下，COX-1 对于 FcεRI 驱动的 CysLT 产生是可有可无的。COX-1 的抑制阻止了 IL-33 诱导的细胞外信号相关激酶的磷酸化，这是胞质型磷脂酶 A 的上游效应物，通过外源性 PGH 恢复，这意味着 COX-1 的作用需要其催化功能。在一种 MC 激活由 IL-33 驱动的 AERD 模型中，COX-1 选择性拮抗剂的给药完全阻止了 PGD 和 LTC 的产生。
MC 内在的 COX-1 放大了先天 2 型免疫中的 IL-33 诱导的激活，这可能有助于解释阿司匹林加重的呼吸道疾病患者中对非选择性 COX 抑制剂治疗脱敏的现象。
