Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma.
Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma.
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IL-23和IL-17在急性肺曲霉病和过敏性哮喘中产生嗜酸性粒细胞作为免疫调节效应细胞的中心作用。
DOI：
10.1371/journal.ppat.1006175
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发表时间：
2017-01
期刊：
影响因子：
6.7
通讯作者：
Levitz SM
中科院分区：
文献类型：
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作者：
Guerra ES;Lee CK;Specht CA;Yadav B;Huang H;Akalin A;Huh JR;Mueller C;Levitz SM
烟曲霉在免疫受损的宿主中会引起侵袭性肺部疾病，在特应性个体中会引起过敏性哮喘。我们研究了肺嗜酸性粒细胞在这些真菌疾病中的作用。通过体内细胞内细胞因子染色和共聚焦显微镜观察到，嗜酸性粒细胞是IL-23和IL-17的局部来源。值得注意的是，缺乏嗜酸性粒细胞的小鼠肺组织中IL-23p19+细胞的百分比降低了95%，肺灌洗液中的IL-23异二聚体也显著减少。嗜酸性粒细胞在体内杀死烟曲霉分生孢子。嗜酸性粒细胞减少的小鼠死亡率较高，炎性单核细胞募集减少，分生孢子攻击后肺巨噬细胞的扩张减少。所有这些功能都强调了嗜酸性粒细胞在急性曲霉病中的潜在保护作用。鉴于IL-17在哮喘发病机制中的假定作用，我们评估了嗜酸性粒细胞是否可以作为IL-23和IL-17的来源，在小鼠对烟曲霉菌抗原或卵清蛋白(OVA)致敏的模型中。我们在两种过敏模型中都发现了IL-23p19+IL-17AF+嗜酸性粒细胞。此外，近95%的IL-23p19+细胞和90%的IL-17AF+细胞被鉴定为嗜酸性粒细胞。这些数据在急性和过敏性曲霉病中建立了一个新的范例，其中嗜酸性粒细胞不仅作为效应细胞，而且作为免疫调节细胞驱动IL-23/IL-17轴，并有助于炎性细胞的募集。这种机会性真菌烟曲霉会引起一系列疾病，从严重免疫抑制者的侵袭性曲霉病到特应性个体的过敏性哮喘。在这里，我们探讨了嗜酸性粒细胞在侵袭性肺曲霉菌病和哮喘小鼠模型中对宿主防御和发病机制的贡献。我们发现，在曲霉病模型和卵清蛋白诱导哮喘模型中，嗜酸性粒细胞共同产生细胞因子IL-23和IL-17。嗜酸性粒细胞在体内杀死了烟曲霉的分生孢子，缺乏嗜酸性粒细胞的小鼠更容易患上侵袭性曲霉病。这些观察表明，嗜酸性粒细胞在防御侵袭性肺曲霉菌病方面的作用比迄今所认识的更显著，并将嗜酸性粒细胞来源的IL-23和IL-17确定为过敏性哮喘的潜在治疗靶点。
Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with conidia. All of these functions underscore a potential protective role for eosinophils in acute aspergillosis. Given the postulated role for IL-17 in asthma pathogenesis, we assessed whether eosinophils could act as sources of IL-23 and IL-17 in models where mice were sensitized to either A. fumigatus antigens or ovalbumin (OVA). We found IL-23p19+ IL-17AF+ eosinophils in both allergic models. Moreover, close to 95% of IL-23p19+ cells and >90% of IL-17AF+ cells were identified as eosinophils. These data establish a new paradigm in acute and allergic aspergillosis whereby eosinophils act not only as effector cells but also as immunomodulatory cells driving the IL-23/IL-17 axis and contributing to inflammatory cell recruitment. The opportunistic fungus, Aspergillus fumigatus, causes a spectrum of diseases ranging from invasive aspergillosis in the severely immunosuppressed to allergic asthma in atopic individuals. Here we explored the contribution of eosinophils, a type of white blood cell, to host defenses and pathogenesis in murine models of invasive pulmonary aspergillosis and asthma. We found eosinophils co-produce the cytokines IL-23 and IL-17 in both aspergillosis models as well as a model of OVA-induced asthma. Eosinophils killed the conidia (spores) of A. fumigatus in vivo and mice that lacked eosinophils were more susceptible to invasive aspergillosis. These observations suggest eosinophils play a more prominent role in defenses against invasive pulmonary aspergillosis than heretofore appreciated and identify eosinophil-derived IL-23 and IL-17 as potential therapeutic targets in allergic asthma.