Gordon Erin D, Simpson Laura J, Rios Cydney L, Ringel Lando, Lachowicz-Scroggins Marrah E, Peters Michael C, Wesolowska-Andersen Agata, Gonzalez Jeanmarie R, MacLeod Hannah J, Christian Laura S, Yuan Shaopeng, Barry Liam, Woodruff Prescott G, Ansel K Mark, Nocka Karl, Seibold Max A, Fahy John V
Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143;
Department of Microbiology and Immunology, University of California San Francisco, CA 94143;
Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8765-70. doi: 10.1073/pnas.1601914113. Epub 2016 Jul 18.
Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an "alarmin" during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, which may operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms.
2型炎症发生在很大一部分哮喘患者中，目前正在开发针对细胞因子的新型疗法来治疗这一群体。在小鼠模型中，白细胞介素-33（IL-33）激活肺部驻留的2型固有淋巴细胞（ILC2s），引发气道2型炎症。在慢性且难以建模的人类哮喘中，IL-33的作用以及导致持续性2型炎症的靶细胞仍不明确。全长IL-33是一种核蛋白，在细胞死亡过程中可能作为一种“警报素”发挥作用，而这一过程在慢性稳定型哮喘中并不常见。我们发现了一种此前未被识别的IL-33活性机制，该机制涉及可变转录剪接，可能在稳定型哮喘中发挥作用。在人气道上皮细胞中，IL-33转录本的可变剪接始终存在，外显子3和4的缺失（Δ外显子3,4）赋予其细胞质定位并促进细胞外分泌，同时保留信号传导能力。在非加重期哮喘患者中，Δ外显子3,4的表达与气道2型炎症密切相关，而全长IL-33则不然。为了进一步明确IL-33在稳定型哮喘中的细胞外作用，我们试图确定其活性的细胞靶点。对痰液细胞进行的综合流式细胞术和RNA测序表明，嗜碱性粒细胞和肥大细胞而非ILC2s是慢性哮喘中2型细胞因子的细胞来源。我们得出结论，IL-33异构体激活嗜碱性粒细胞和肥大细胞，在慢性稳定型哮喘中驱动2型炎症，新型IL-33抑制剂需要阻断所有具有生物活性的异构体。
