Matsuda Kenshiro, Arkwright Peter D, Mori Yasuo, Oikawa Masa-Aki, Muko Ryo, Tanaka Akane, Matsuda Hiroshi
Laboratory of Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan.
Lydia Becker Institute of Immunity and Inflammation, University of Manchester, Manchester M13 9WL, United Kingdom.
J Immunol. 2020 Dec 1;205(11):2959-2967. doi: 10.4049/jimmunol.2000149. Epub 2020 Oct 23.
Extensive activation of mast cells is the major switch that triggers systemic anaphylaxis, resulting in the subsequent release of anaphylactic mediators into circulation. We previously demonstrated that rapid changes in oxygen tension lead to mast cell degranulation, and the released tryptase triggers retinal angiogenesis in a murine oxygen-induced retinopathy model. However, whether a rapid shift from hyperoxia to normoxia (relative hypoxic stress) is a risk factor for systemic anaphylaxis remains unknown. In this study, we demonstrated that the relative hypoxia stress induces systemic mast cell activation via transient receptor potential ankyrin 1 (TRPA1) channels, which immediately leads to hypothermia and increased vascular permeability in adult mice. Although mast cell-deficient or TRPA1-deficient mice did not exhibit anaphylactic symptoms following a rapid sift to normoxia, preinjection with bone marrow-derived cultured mast cells (BMCMCs) derived from wild-type TRPA1-expressing mice restored anaphylactic responses. In addition, we found that the rapid reductions in oxygen tension in a culture atmosphere triggered the degranulation of BMCMCs derived from wild-type TRPA1-expressing mice but not that of BMCMCs derived from TRPA1-deficient mice. In human LAD2 mast cells, the relative hypoxic stress led to the degranulation, which was suppressed by the addition of a TRPA1 inhibitor. Gradual reductions from hyperoxia to normoxia led to no anaphylactic symptoms. Our results demonstrated that TRPA1-triggered mast cell degranulation is a novel pathway that induces anaphylactic shock without Ag-Ab reactions. These findings introduce a potential role for oxygen in inducing mast cell-dependent anaphylaxis and highlight the need to reconsider chronic pure oxygen therapy for anoxic diseases.
肥大细胞的广泛激活是引发全身性过敏反应的主要开关，会导致过敏介质随后释放到循环系统中。我们之前证明，氧张力的快速变化会导致肥大细胞脱颗粒，并且释放的类胰蛋白酶在小鼠氧诱导性视网膜病变模型中触发视网膜血管生成。然而，从高氧快速转变为常氧（相对低氧应激）是否是全身性过敏反应的危险因素仍不清楚。在本研究中，我们证明相对低氧应激通过瞬时受体电位锚蛋白1（TRPA1）通道诱导全身性肥大细胞激活，这会立即导致成年小鼠体温过低和血管通透性增加。尽管肥大细胞缺陷或TRPA1缺陷的小鼠在快速转变为常氧后未表现出过敏症状，但预先注射源自表达野生型TRPA1的小鼠的骨髓来源培养肥大细胞（BMCMC）可恢复过敏反应。此外，我们发现培养环境中氧张力的快速降低会触发源自表达野生型TRPA1的小鼠的BMCMC脱颗粒，但不会触发源自TRPA1缺陷小鼠的BMCMC脱颗粒。在人LAD2肥大细胞中，相对低氧应激导致脱颗粒，添加TRPA1抑制剂可抑制这种脱颗粒。从高氧逐渐降低到常氧不会导致过敏症状。我们的结果表明，TRPA1触发的肥大细胞脱颗粒是一种在没有抗原-抗体反应的情况下诱导过敏性休克的新途径。这些发现揭示了氧在诱导肥大细胞依赖性过敏反应中的潜在作用，并强调有必要重新考虑针对缺氧疾病的慢性纯氧疗法。
