Key Points 12/15-Lipoxygenase is required for inflammatory responses during fungal infection. 12/15-Lipoxygenase is required for neutrophil granulopoiesis. Development of invasive aspergillosis correlates with impairments in innate immunity. We and others have recently shown that arachidonic acid metabolism pathways, specifically the cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways, participate in the induction of protective innate immune responses during invasive aspergillosis. Based on the high degree of cooperation and interconnection within the eicosanoid network, we hypothesized that 12/15-LOX is also active during invasive aspergillosis. We report in this study that mice deficient in the gene encoding 12/15-LOX (Alox15) are profoundly susceptible to invasive aspergillosis. Decreased survival correlated with increased fungal burden and evidence of increased lung damage. These defects were associated with very early (6 and 12 h) 12/15-LOX–dependent inflammatory cytokine (IL-1α, IL-1β, and TNF-α) and chemokine (CCL3 and CCL4) production. Neutrophil levels in the lung were blunted in the absence of 12/15-LOX, although neutrophil antifungal activity was intact. However, lower neutrophil levels in the lungs of Alox15−/− mice were not a result of impaired recruitment or survival; rather, Alox15−/− mice demonstrated impaired neutrophil granulopoiesis in the bone marrow intrinsically and after fungal exposure. Employing a lower inoculum to allow for better survival allowed the identification of 12/15-LOX–dependent induction of IL-17A and IL-22. Impaired IL-17A and IL-22 production correlated with reduced invariant NKT cell numbers as well as lower IL-23 levels. Together, these data indicate that 12/15-LOX is a critical player in induction of the earliest aspects of the innate immune response to Aspergillus fumigatus.

中文翻译：

---

12/15-脂氧合酶缺乏会损害中性粒细胞粒细胞生成和肺对烟曲霉的炎症反应

关键点 真菌感染期间的炎症反应需要 12/15-脂氧合酶。中性粒细胞生成需要 12/15-脂氧化酶。侵袭性曲霉病的发展与先天免疫受损有关。我们和其他人最近表明，花生四烯酸代谢途径，特别是环氧合酶-2 (COX-2) 和 5-脂氧合酶 (5-LOX) 途径，参与了侵袭性曲霉病过程中保护性先天免疫反应的诱导。基于类二十烷酸网络内的高度合作和互连，我们假设 12/15-LOX 在侵袭性曲霉病期间也活跃。我们在这项研究中报告说，缺乏 12/15-LOX (Alox15) 编码基因的小鼠极易感染侵袭性曲霉病。存活率降低与真菌负担增加和肺损伤增加的证据相关。这些缺陷与非常早期（6 和 12 小时）12/15-LOX 依赖性炎症细胞因子（IL-1α、IL-1β 和 TNF-α）和趋化因子（CCL3 和 CCL4）的产生有关。在没有 12/15-LOX 的情况下，肺中的中性粒细胞水平会减弱，尽管中性粒细胞的抗真菌活性是完整的。然而，Alox15-/- 小鼠肺中较低的中性粒细胞水平并不是募集或存活受损的结果。相反，Alox15-/- 小鼠表现出骨髓中中性粒细胞的内在性和真菌暴露后受损。使用较低的接种物以允许更好的存活允许鉴定 IL-17A 和 IL-22 的 12/15-LOX 依赖性诱导。IL-17A 和 IL-22 产生受损与不变 NKT 细胞数量减少以及 IL-23 水平降低相关。总之，这些数据表明 12/15-LOX 是诱导对烟曲霉的先天免疫反应最早方面的关键参与者。