IL-33, IL-25 and TSLP contribute to development of fungal-associated protease-induced innate-type airway inflammation
IL-33, IL-25 and TSLP contribute to development of fungal-associated protease-induced innate-type airway inflammation
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DOI：
10.1038/s41598-018-36440-x
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发表时间：
2018-12-21
影响因子：
4.6
通讯作者：
Nakae, Susumu
中科院分区：
文献类型：
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作者：
Hiraishi, Yoshihisa;Yamaguchi, Sachiko;Nakae, Susumu
从屋尘螨和植物中提取的某些蛋白酶被认为是通过破坏上皮细胞之间的紧密连接而引发过敏性呼吸道炎症。众所周知，吸入屋尘螨来源的Der p1和/或木瓜来源的木瓜酶等蛋白酶会导致幼小鼠的呼吸道嗜酸性粒细胞增多，甚至在缺乏获得性免疫细胞(如T、B和NKT细胞)的RAG缺陷小鼠中也是如此。相比之下，对于环境中普遍存在的腐生真菌曲霉菌来源的蛋白酶(真菌相关蛋白酶；FAP)在过敏性呼吸道嗜酸性粒细胞增多症的发生中的可能参与，人们知之甚少。在这里，我们发现幼鼠吸入FAP会导致依赖于蛋白酶激活受体-2(PAR2)的呼吸道嗜酸性粒细胞增多，而不是TLR2和TLR4。这些发现表明，FAP的蛋白酶活性，而不是FAP中的内毒素，在环境中是重要的。此外，嗜酸性粒细胞增多是由先天免疫细胞(ILCs)(如先天淋巴细胞)而不是后天免疫细胞(如T、B和NKT细胞)所介导。IL-33、IL-25和胸腺基质淋巴生成素(TSLP)参与了FAP诱导的ILC介导的气道嗜酸性粒细胞增多症的诱导，而IL-33而不是IL-25和/或TSLP对本模型中的嗜酸性粒细胞增多症起关键作用。我们的发现提高了我们对FAP诱导呼吸道炎症的分子机制的理解。
Certain proteases derived from house dust mites and plants are considered to trigger initiation of allergic airway inflammation by disrupting tight junctions between epithelial cells. It is known that inhalation of proteases such as house dust mite-derived Der p1 and/or papaya-derived papain caused airway eosinophilia in naive mice and even in Rag-deficient mice that lack acquired immune cells such as T, B and NKT cells. In contrast, little is known regarding the possible involvement of proteases derived from Aspergillus species (fungal-associated proteases; FAP), which are ubiquitous saprophytic fungi in the environment, in the development of allergic airway eosinophilia. Here, we found that inhalation of FAP by naive mice led to airway eosinophilia that was dependent on protease-activated receptor-2 (PAR2), but not TLR2 and TLR4. Those findings suggest that the protease activity of FAP, but not endotoxins in FAP, are important in the setting. In addition, development of that eosinophilia was mediated by innate immune cells (ILCs) such as innate lymphoid cells, but not by acquired immune cells such as T, B and NKT cells. Whereas IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) are involved in induction of FAP-induced ILC-mediated airway eosinophilia, IL-33-rather than IL-25 and/or TSLP-was critical for the eosinophilia in our model. Our findings improve our understanding of the molecular mechanisms involved in induction of airway inflammation by FAP.