Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany.
Department of Medicine 3, University Hospital of Erlangen, Erlangen, Germany.
Front Immunol. 2020 May 7;11:691. doi: 10.3389/fimmu.2020.00691. eCollection 2020.
Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6 ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions and using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.
囊性纤维化患者患有进行性的、常致命的肺部疾病，其基础是慢性感染、局部积累的免疫细胞和肺组织重塑之间的复杂相互作用。尽管 2 型固有淋巴细胞 (ILC2) 作为肺部炎症的关键启动子，但我们对它们在囊性纤维化发病机制中的作用的理解仍不完整。在这里，我们报告囊性纤维化患者血液中循环的 CCR6+ILC2 明显减少，这与疾病严重程度高和肺功能衰竭进展显著相关，强烈提示 ILC2 从外周血向囊性纤维化患者慢性炎症肺组织的归巢增加。在功能水平上，CCR6 配体 CCL20 被鉴定为炎症条件下促进肺定向 ILC2 迁移的有效诱导剂，我们使用了一种新的人源化小鼠模型，该模型通过光片荧光显微镜可视化肺部累积的人 ILC2。在肺部，血液来源的人 ILC2 能够增加局部嗜酸性粒细胞和中性粒细胞的积累，并诱导肺型 VI 型胶原表达的显著上调。对原代人肺成纤维细胞的研究进一步揭示了 ILC2 衍生的 IL-4 和 IL-13 作为这种诱导型 VI 型胶原表达的重要介质。综上所述，这些结果表明，囊性纤维化气道中病理性增加的 CCL20 水平诱导循环人 ILC2 的 CCR6 介导的肺归巢。随后 ILC2 的激活触发局部产生型 VI 型胶原，从而可能驱动细胞外基质重塑，潜在影响囊性纤维化患者的肺组织破坏。因此，调节循环 ILC2 的肺归巢能力及其局部效应功能为囊性纤维化的治疗开辟了新的治疗途径。
