CardioRespiratory Research Group, Division of Respirology, Department of Medicine, and.
Department of Pulmonary Medicine, Graduate School of Medical & Dental Sciences, Kagoshima University, Kagoshima, Japan.
Am J Respir Crit Care Med. 2020 Oct 15;202(8):1105-1114. doi: 10.1164/rccm.201909-1722OC.
Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial cell-derived cytokine signaling, implicating alternate stimulatory pathways. DR3 (death receptor 3), a member of the tumor necrosis factor receptor superfamily, is expressed on ILC2s. Genome-wide association studies report an association between DR3 ligand, TL1A (tumor necrosis factor-like protein 1A), and chronic inflammatory conditions. We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma. Stable subjects with mild asthma were subject to allergen inhalation challenge, and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from subjects with mild asthma and subjects with prednisone-dependent severe eosinophilic asthma. There was a significant increase in sputum DR3 ILC2s 24 hours after allergen challenge, and DR3 expression on ILC2s was upregulated by IL-2, IL-33, or TSLP . Stimulation with TL1A significantly increased IL-5 expression by ILC2s and was attenuated by dexamethasone, an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 hours after allergen challenge in subjects with mild asthma but were significantly greater in those with severe eosinophilic asthma. The highest levels were detected in subjects with severe asthma with airway autoimmune responses. C1q immune complexes from the sputa of subjects with severe asthma with high autoantibody levels stimulated TL1A production by monocytes. The TL1A/DR3 axis is a costimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
2 型固有淋巴细胞 (ILC2) 对于 2 型炎症至关重要。在哮喘的鼠模型中，一些 ILC2 在没有上皮细胞衍生的细胞因子信号的情况下仍然被激活，这暗示了替代的刺激途径。DR3（死亡受体 3）是肿瘤坏死因子受体超家族的成员，在 ILC2 上表达。全基因组关联研究报告 DR3 配体 TL1A（肿瘤坏死因子样蛋白 1A）与慢性炎症性疾病之间存在关联。我们研究了气道 ILC2 生物学中 TL1A/DR3 轴在嗜酸性粒细胞性哮喘中的作用。稳定的轻度哮喘患者接受变应原吸入挑战，评估痰细胞上的 DR3 表达。我们研究了细胞因子对 ILC2 上 DR3 表达的调节作用和类固醇敏感性。评估了轻度哮喘患者和依赖泼尼松的严重嗜酸性粒细胞性哮喘患者痰中的气道 TL1A。变应原挑战后 24 小时，痰中 DR3 ILC2 显著增加，IL-2、IL-33 或 TSLP 上调 ILC2 上的 DR3 表达。TL1A 刺激显著增加 ILC2 中 IL-5 的表达，并且被地塞米松减弱，而在 TSLP 存在下，该作用被否定。轻度哮喘患者变应原挑战后 24 小时气道 TL1A 水平增加，但严重嗜酸性粒细胞性哮喘患者增加更为明显。在具有气道自身免疫反应的严重哮喘患者中检测到最高水平。来自高自身抗体水平的严重哮喘患者的痰液中的 C1q 免疫复合物刺激单核细胞产生 TL1A。TL1A/DR3 轴是哮喘中 ILC2 的共刺激物，特别是在易发生自身免疫反应的患者的气道中。
