Activation of group 2 innate lymphoid cells exacerbates and confers corticosteroid resistance to mouse nasal type 2 inflammation
Activation of group 2 innate lymphoid cells exacerbates and confers corticosteroid resistance to mouse nasal type 2 inflammation
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DOI：
10.1093/intimm/dxx030
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发表时间：
2017-05-01
影响因子：
4.4
通讯作者：
Yoshimoto, Tomohiro
中科院分区：
文献类型：
--
作者：
Morikawa, Taiyo;Fukuoka, Ayumi;Yoshimoto, Tomohiro
皮质类固醇耐药的 ILC2 会加剧鼻腔 T(h)2 炎症。T(h)2 细胞和第 2 组先天淋巴细胞 (ILC2) 都会导致过敏性疾病。然而，它们在鼻过敏性疾病中的确切作用和关系尚不清楚。在这项研究中，我们研究了 T(h)2 细胞和 ILC2 在鼻过敏性疾病小鼠模型中的合作。为了差异化激活鼻粘膜中的 T(h)2 细胞和/或 ILC2，小鼠鼻内施用卵清蛋白 (OVA) 抗原、木瓜蛋白酶、ILC2 激活剂或两者，持续 2 周。最终攻击后24小时评估鼻粘膜上皮厚度和嗜酸性粒细胞数量。鼻内给予 OVA 和木瓜蛋白酶分别优先激活鼻子中的 T(h)2 细胞和 ILC2。 OVA和木瓜蛋白酶均增加了鼻上皮厚度和嗜酸性粒细胞数量，并且它们的共同给药显着增强了症状。尽管T/B细胞缺陷小鼠表现出由OVA或OVA加木瓜蛋白酶引起的鼻部症状严重减轻，但小鼠仍然表现出轻微的木瓜蛋白酶引起的鼻部症状。在 ILC2 缺陷小鼠中，OVA 加木瓜蛋白酶引起的鼻部症状被抑制到与单独使用 OVA 相同的水平。同样，IL-33 和 ST2 缺陷小鼠表现出 OVA 加木瓜蛋白酶诱导的鼻症状减轻。 IL-5仅诱导嗜酸性粒细胞增多，但IL-13导致鼻上皮增厚和OVA加木瓜蛋白酶诱导的嗜酸性粒细胞增多。地塞米松改善了单独使用 OVA 引起的鼻上皮增厚。然而，OVA加木瓜蛋白酶引起的鼻上皮增厚仅部分地被地塞米松控制。这些结果表明，IL-33/ST2 通路介导的 ILC2 激活通过产生 IL-13 加剧了 T(h)2 细胞诱导的鼻部炎症。尽管单独 T(h)2 细胞诱导的鼻部炎症可通过皮质类固醇治疗得到控制，但 ILC2 的激活会导致治疗抵抗。因此，ILC2 及其激活剂可能成为难治性鼻过敏性疾病的治疗靶点。
Corticosteroid-resistant ILC2s exacerbate nasal T(h)2 inflammation.Both T(h)2 cells and group 2 innate lymphoid cells (ILC2s) contribute to allergic diseases. However, their exact role and relationship in nasal allergic disorders are unclear. In this study, we investigated the cooperation of T(h)2 cells and ILC2s in a mouse model of nasal allergic disorder. To differentially activate T(h)2 cells and/or ILC2s in nasal mucosa, mice were intra-nasally administered ovalbumin (OVA) antigen, papain, an ILC2-activator, or both for 2 weeks. Epithelial thickness and number of eosinophils in the nasal mucosa were evaluated at 24 h after the final challenge. Intra-nasal administration of OVA and papain preferentially activated T(h)2 cells and ILC2s, respectively, in the nose. Both OVA and papain increased the nasal epithelial thickness and number of eosinophils, and their coadministration significantly enhanced the symptoms. Although T-/B-cell-deficient mice showed severely decreased nasal symptoms induced by OVA or OVA-plus-papain, the mice still showed slight papain-induced nasal symptoms. In ILC2-deficient mice, OVA-plus-papain-induced nasal symptoms were suppressed to the same level as OVA-alone. Similarly, IL-33- and ST2-deficient mice showed decreased OVA-plus-papain-induced nasal symptoms. IL-5 induced eosinophilia only, but IL-13 contributed to both nasal epithelial thickening and eosinophilia induced by OVA-plus-papain. Dexamethasone ameliorated OVA-alone-induced nasal epithelial thickening. However, OVA-plus-papain-induced nasal epithelial thickening was only partially controlled by dexamethasone. These results demonstrate that IL-33/ST2-pathway-mediated ILC2 activation exacerbated T(h)2-cell-induced nasal inflammation by producing IL-13. Although T(h)2-cell-alone-induced nasal inflammation was controlled by corticosteroid treatment, the activation of ILC2s conferred treatment resistance. Therefore, ILC2s and their activators could be therapeutic targets for treatment-refractory nasal allergic disorders.