Immunopathogenesis in fungal asthma

真菌性哮喘的免疫发病机制

• 批准号: 8982244
• 负责人: Chad Steele
• 金额: $ 43.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-08 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8982244
• 关键词: Acute; Address; Affect; Allergic; Aspergillosis; Aspergillus fumigatus; Asthma; CCL17 gene; Cell Wall; Cells; Chitin; Chronic; Collaborations; Data; Defect; Development; Disease; Epithelial Cells; Exposure to; Family member; Glucans; Growth; Health; Human; Hypersensitivity skin testing; Individual; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-1 alpha; Interleukin-17; Laboratories; Link; Liquid substance; Lung; Mannans; Measures; Mediating; Melanins; Modeling; Molds; Mus; National Heart, Lung, and Blood Institute; Pathogenesis; Phosphoric Monoester Hydrolases; Pilot Projects; Predisposition; Production; Proteins; Psoriasis; Reporter; Reporting; Research; Research Personnel; Respiratory physiology; Role; Severities; Signal Transduction; Source; Sputum; Surface; Translating; Trehalose; Universities; asthmatic; beta-Glucans; chemokine; cytokine; dectin 1; defined contribution; forest; fungus; improved; inorganic phosphate; interleukin-22; interleukin-23; medical schools; mutant; novel; programs; response

DESCRIPTION (provided by applicant): Sensitization to fungi, such as the mold Aspergillus fumigatus, is increasingly becoming linked with asthma severity. Over the last several years, our laboratory has identified protective roles for Dectin-1 mediated beta-glucan recognition and Dectin-1 dependent IL-17A and IL-22 production during acute challenge with A. fumigatus (invasive aspergillosis, IA). Unexpectedly, in a chronic A. fumigatus exposure model of fungal asthma (A. fumigatus associated asthma, AFAA), we recently reported that the absence of Dectin-1 or IL-22 resulted in markedly improved lung function in the presence of reductions in multiple pro-allergic and pro- inflammatory mediators (Lilly et al., J Immunol 189:3653; 2012). Our studies further suggested that reduced severity of AFAA observed in the absence of Dectin-1 or IL-22 correlated with lower levels of the pro-allergic and known asthma susceptibility cytokine IL-33 (IL-1F11). Indeed, preliminary data from mice deficient in IL- 33R show reduced AFAA severity. However, a link between IL-22 and IL-33 is not known. In preliminary data, we show that during AFAA, production of IL-1�IL-1F1) is dependent on IL-22. We further show that the novel IL-1 family member IL-36? (IL-1F9) was upregulated in the lungs more than 100-fold during IA, yet significantly reduced in Il22-/- mice during both IA and AFAA. IL-36? can induce IL-1�n the lungs and IL-1�as been recently reported to induce IL-33 production by epithelial cells, suggesting a possible IL-22IL-36?IL-1�L-33 axis in immunopathogenesis during fungal asthma. In new preliminary studies, we show that the absence of IL-36R signaling or neutralization of IL-1�eads to lower CCL17 levels during AFAA. We further show that chronic exposure to an A. fumigatus trehalose-6-phosphate phosphatase mutant (orlA), which has elevated cell wall alpha-glucan levels, resulted in more severe AFAA (higher induction of IL-22, IL-33 and CCL17). These results suggest that recognition of moieties in the A. fumigatus cell wall affects severity of fungal asthma. Finally, in collaboration with the NHLBI-sponsored Severe Asthma Research Program (SARP), we have identified multiple SNPs in Il23, Il17a and Il22 in fungal skin-test (+) asthmatics that correlated with asthma severity. In new pilot studies, we show feasibility of measuring cytokines and chemokines in sputum or BAL fluid from skin test (+) vs. skin test (-) asthmatics and our ability to correlate them with asthma severity. Further studies are required to determine the magnitude by which IL-23, IL-17A and IL-22 levels are modulated in these individuals as well as whether the levels of IL-36?, IL-1�nd IL-33 are also modulated. Collectively, our central hypothesis is that IL-22-induced IL-1 family members contribute to immunopathogenesis during fungal asthma. To address this hypothesis, we have proposed the following three independent, interrelated Aims: (1) elucidate IL-22-dependent mechanisms contributing to immunopathogenesis during fungal asthma, (2) examine the contribution of specific fungal cell wall moieties in IL-22 induction and fungal asthma severity and (3) define the IL-23/IL-17A/IL-22 axis in human asthmatics that are skin-test (+) for fungi.

描述（由申请人提供）：对真菌（例如烟曲霉）的过敏与哮喘严重程度越来越相关。在过去的几年中，我们的实验室已经确定了在烟曲霉（侵袭性曲霉病，IA）急性攻击期间 Dectin-1 介导的 β-葡聚糖识别以及 Dectin-1 依赖性 IL-17A 和 IL-22 产生的保护作用。出乎意料的是，在真菌哮喘的慢性烟曲霉暴露模型（烟曲霉相关性哮喘，AFAA）中，我们最近报道，在多种促过敏和促炎介质减少的情况下，Dectin-1或IL-22的缺失导致肺功能显着改善（Lilly等人，JImmunol 189：3653；2012）。我们的研究进一步表明，在缺乏 Dectin-1 或 IL-22 的情况下观察到的 AFAA 严重程度降低与促过敏且已知的哮喘易感性细胞因子 IL-33 (IL-1F11) 水平较低相关。事实上，IL-33R 缺陷小鼠的初步数据显示 AFAA 严重程度降低。然而，IL-22 和 IL-33 之间的联系尚不清楚。在初步数据中，我们表明在 AFAA 期间，IL-1（IL-1F1）的产生依赖于 IL-22。我们进一步证明了新的IL-1家族成员IL-36？ (IL-1F9) 在 IA 期间在肺部表达上调超过 100 倍，但在 IA 和 AFAA 期间在 Il22-/- 小鼠中显着降低。 IL-36？可以诱导肺部的 IL-1，并且最近报道 IL-1 可以诱导上皮细胞产生 IL-33，这表明真菌性哮喘期间的免疫发病机制中可能存在 IL-22、IL-36、IL-1、L-33 轴。在新的初步研究中，我们表明，IL-36R 信号传导的缺失或 IL-1� 的中和会导致 AFAA 期间 CCL17 水平降低。我们进一步表明，长期暴露于烟曲霉海藻糖-6-磷酸磷酸酶突变体（orlA）（其细胞壁α-葡聚糖水平升高）会导致更严重的AFAA（IL-22、IL-33和CCL17的诱导更高）。这些结果表明烟曲霉细胞壁中的部分的识别影响真菌性哮喘的严重程度。最后，我们与 NHLBI 赞助的严重哮喘研究计划 (SARP) 合作，在真菌皮试 (+) 哮喘患者的 Il23、Il17a 和 Il22 中发现了多个与哮喘严重程度相关的 SNP。在新的试点研究中，我们展示了通过皮试（+）与皮试（-）哮喘患者测量痰液或支气管肺泡灌洗液中细胞因子和趋化因子的可行性，以及我们将它们与哮喘严重程度相关联的能力。需要进一步的研究来确定这些个体中 IL-23、IL-17A 和 IL-22 水平调节的程度以及 IL-36、IL-1 和 IL-33 的水平是否也受到调节​​。总的来说，我们的中心假设是 IL-22 诱导的 IL-1 家族成员有助于真菌哮喘期间的免疫发病机制。为了解决这一假设，我们提出了以下三个独立、相互关联的目标：（1）阐明在真菌性哮喘期间导致免疫发病的IL-22依赖性机制，（2）检查特定真菌细胞壁部分在IL-22诱导和真菌性哮喘严重程度中的贡献，以及（3）定义人类中的IL-23/IL-17A/IL-22轴 真菌皮试 (+) 的哮喘患者。