Immunopathogenesis in fungal asthma

真菌性哮喘的免疫发病机制

• 批准号: 9187993
• 负责人: Chad Steele
• 金额: $ 43.11万
• 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/9187993
• 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; 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; public health relevance; 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)：对真菌的敏感度，如霉菌烟曲霉，越来越多地与哮喘的严重程度联系在一起。在过去的几年里，我们的实验室已经确定了Dectin-1介导的β-葡聚糖识别以及Dectin-1依赖的IL-17A和IL-22在烟曲霉(侵袭性曲霉病，IA)急性攻击时的保护作用。出乎意料的是，在一个真菌哮喘的慢性烟曲霉菌暴露模型(A.fumigatus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的缺失导致明显的肺功能改善(Lilly等，J免疫189：3653；2012)。我们的研究进一步表明，在没有Dectin-1或IL-22的情况下，AFAA的严重程度降低与促过敏和已知的哮喘易感细胞因子IL-33(IL-1F11)水平降低有关。事实上，来自IL-33R缺陷小鼠的初步数据显示，AFAA的严重程度有所降低。然而，IL-22和IL-33之间的联系尚不清楚。在初步的数据中，我们发现在急性再生障碍性贫血中，IL-1�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期间在肺中上调100倍以上，但在IL22-/-小鼠中在IA和AFAA期间显著降低。IL-36？可诱导肺部IL-1�和IL-1�诱导上皮细胞产生IL-33，提示IL-22IL-36、IL-1�L-33轴可能参与了真菌性哮喘的免疫发病机制。在新的初步研究中，我们发现，在AFAA期间，IL-36R信号的缺失或IL-1�EAD的中和可以降低CCL17的水平。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，导致更严重的AFAA(更高的IL-22、IL-33和CCL17的诱导)。这些结果表明，对烟曲霉细胞壁中部分成分的识别会影响真菌性哮喘的严重程度。最后，与NHLBI赞助的重症哮喘研究计划(SARP)合作，我们在真菌皮肤试验(+)哮喘患者中发现了IL23、IL17A和IL22中的多个SNP与哮喘严重程度相关。在新的先导性研究中，我们展示了从皮试(+)与皮试(-)哮喘患者的痰或BAL液中检测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。IL-23、IL-17A和IL-22水平在这些个体中的调节幅度以及IL-36β、IL-1�和IL-33的水平是否也受到调节，还需要进一步的研究。总而言之，我们的中心假设是IL-22诱导的IL-1家族成员在真菌性哮喘的免疫发病机制中做出了贡献。为了解决这一假设，我们提出了以下三个独立且相互关联的目标：(1)阐明IL-22依赖在真菌性哮喘免疫发病机制中的作用；(2)研究特定的真菌细胞壁部分在IL-22诱导和真菌性哮喘严重程度中的作用；(3)确定人类哮喘患者中的IL-23/IL-17A/IL-22轴，即真菌皮肤试验(+)。