Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

中文翻译：

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尽管在真菌相关的过敏性气道炎症中促进了 2 型炎症，几丁质酶 3-like-1 仍能保护气道功能

根据宿主的免疫状态，接触真菌会导致广泛的合并症。慢性接触和对真菌（如烟曲霉）的反应可导致诸如真菌致敏性严重哮喘 (SAFS) 或过敏性支气管肺曲霉病 (ABPA) 等疾病。然而，SAFS 和 ABPA 的病理生理学尚不清楚。在这里，我们报告了几丁质酶样蛋白 YKL-40 在对真菌敏感的人类哮喘患者的肺灌洗液中升高。初步研究表明，缺乏 YKL-40 的鼠类直系同源物，乳房退化蛋白 39（BRP-39，几丁质酶 3 样 1，Chi3l1）的小鼠对烟曲霉的急性感染并不敏感。然而，在真菌相关过敏性气道炎症（真菌性哮喘）的实验模型中，Chi3l1-/- 小鼠气道高反应性 (AHR) 显着增加。令人惊讶的是，Chi3l1-/- 小鼠的 AHR 增加发生在显着降低 2 型反应（嗜酸性粒细胞数量减少和 IL-4、IL-5、IL-33、CCL17 和 CCL22 水平降低）的情况下，尽管 1 型和 17 型反应没有什么不同。AHR 增加与肺组织过碘酸席夫染色的差异、Muc5ac 和 Clca3 表达的差异以及肺水肿的差异无关。骨髓嵌合体研究表明，造血或非造血隔室中 BRP-39 的存在足以控制真菌性哮喘期间的 AHR。总的来说，这些结果表明 BRP-39 在真菌性哮喘期间可以预防 AHR，尽管它会导致 2 型炎症，