Immunopathogenesis in fungal asthma
真菌性哮喘的免疫发病机制
基本信息
- 批准号:9187993
- 负责人:
- 金额:$ 43.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAddressAffectAllergicAspergillosisAspergillus fumigatusAsthmaCCL17 geneCell WallCellsChitinChronicCollaborationsDataDefectDevelopmentDiseaseEpithelial CellsExposure toFamily memberGlucansGrowthHumanHypersensitivity skin testingIndividualInflammation MediatorsInflammatoryInterleukin-1Interleukin-1 alphaInterleukin-17LaboratoriesLinkLiquid substanceLungMannansMeasuresMediatingMelaninsModelingMoldsMusNational Heart, Lung, and Blood InstitutePathogenesisPhosphoric Monoester HydrolasesPilot ProjectsPredispositionProductionProteinsPsoriasisReporterReportingResearchResearch PersonnelRespiratory physiologyRoleSeveritiesSignal TransductionSourceSputumSurfaceTranslatingTrehaloseUniversitiesasthmaticbeta-Glucanschemokinecytokinedectin 1defined contributionforestfungusimprovedinorganic phosphateinterleukin-22interleukin-23medical schoolsmutantnovelprogramspublic health relevanceresponse
项目摘要
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(+)。
项目成果
期刊论文数量(0)
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Chad Steele其他文献
Chad Steele的其他文献
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{{ truncateString('Chad Steele', 18)}}的其他基金
Biology of innate IL-22 during lung fungal infection
肺部真菌感染期间先天性 IL-22 的生物学
- 批准号:
10643901 - 财政年份:2017
- 资助金额:
$ 43.11万 - 项目类别:
Biology of innate IL-22 during lung fungal infection
肺部真菌感染期间先天性 IL-22 的生物学
- 批准号:
10316508 - 财政年份:2017
- 资助金额:
$ 43.11万 - 项目类别:
Biology of innate IL-22 during lung fungal infection
肺部真菌感染期间先天性 IL-22 的生物学
- 批准号:
10474632 - 财政年份:2017
- 资助金额:
$ 43.11万 - 项目类别:
Eosinophils and lung immunity to Pneumocystis
嗜酸性粒细胞和肺对肺孢子菌的免疫
- 批准号:
8515522 - 财政年份:2012
- 资助金额:
$ 43.11万 - 项目类别:
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