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

基本信息

批准号：
10643901
负责人：
Chad Steele
金额：
$ 38万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643901
关键词：
Acids Alveolar Amplifiers Arachidonate 15-Lipoxygenase Arachidonate 5-Lipoxygenase Aspergillus fumigatus Asthma Attention Biological Products Biology Bone Marrow Cells Cellularity Chronic Obstructive Pulmonary Disease Colitis Cytochrome P450 Data Dendritic Cells Development Dinoprost Dinoprostone Disease Eicosanoids Enzymes Epithelial Cells Epithelium Flow Cytometry Funding Generations Host Defense Human Hydroxyeicosatetraenoic Acids IL17 gene ITGAX gene Immune Immune response Immunity Immunocompromised Host Immunohistochemistry Impairment Individual Infection Inflammatory Inflammatory Response LOX gene Lipids Lipoxygenase LoxP-flanked allele Lung Lung diseases Lung infections Mediating Molds Mus Mycoses Myelogenous Myeloid Cells Outcome Pathway interactions Population Predisposition Production Prostaglandin D2 Prostaglandins Psoriasis Receptor Signaling Recombinants Regulation Reporter Reporting Role Signal Transduction Source Structure of parenchyma of lung Work alveolar type II cell cytokine design gastrointestinal helminth infection immunoregulation immunosuppressed in vivo interleukin-22 lipid mediator lipidome lipidomics neutrophil novel response therapeutic target

项目摘要

Aspergillus fumigatus is an opportunistic mold that causes difficult to treat invasive fungal infections in immunocompromised and immunosuppressed individuals, often resulting in a lethal outcome. The objective of this competitive renewal R01 is to build upon our recent work that has uncovered roles for bioactive lipid mediators in immune responses during lung fungal infection with A. fumigatus. In the previous funding period, we made three novel findings: (i) IL-33 receptor signaling negatively regulated immunoprotective type 17 responses during A. fumigatus infection, (ii) the eicosanoid PGE2 positively regulated IL-17A and IL-22 induction and (3) IL-33 receptor signaling negatively regulated PGE2 production (J Immunol 99:2140-2148, 2017). In other work supported by this proposal, we reported that deficiency in 12/15-lipoxygenase (12/15-LOX, Alox15-/-) resulted in impaired inflammatory responses and profound susceptibility to lung infection with A. fumigatus (J Immunol 204:1849-1858, 2020). Intriguingly, a mechanism of susceptibility we observed in Alox15-/- mice was impaired neutrophil maturation in the bone marrow. Our findings overall have prompted some interesting questions: (i) how does IL-33 modulate PGE2 during lung fungal infection? (ii) does IL-33 regulate the production of other bioactive lipids? (iii) can bioactive lipids other than PGE2 modulate immune responses during infection with A. fumigatus? (iv) are specific bioactive lipids required for or negatively regulate neutrophil maturation during infection? Lipidomic analysis of lung tissue from A. fumigatus exposed mice demonstrates that IL-33 signaling is a profound negative regulator of multiple bioactive lipid classes, including prostaglandins, hydroxydocosahexaenoic acids (HDHAs), hydroxyeicosapentaenoic acids (HEPEs) and hydroxyeicosatetraenoic acids (HETEs). Data further shows the Alox15-/- mice have a unique lung lipid signature during A. fumigatus infection, one that may function to modulate neutrophil-mediated immunity to A. fumigatus. In other studies, employing Il33flox/flox-eGFP reporter mice and a combination of flow cytometry and fluorescent immunohistochemistry, we show that dendritic cells and neutrophils are immune cell sources of IL-33 whereas alveolar type II cells are the primary non-immune cell source of IL-33 in the lung during A. fumigatus infection. Recent studies suggest that the cellular source of IL-33 (i.e. myeloid vs. epithelial) may have a dramatic effect on the type of immune response. Overall, our hypothesis is that bioactive lipids, regulated by cytokines such as IL-33 and enzymes such as 12/15/-LOX, tune the inflammatory response during A. fumigatus lung infection. The specific aims of the proposal are: (1) to determine the mechanism(s) associated with and function of IL-33 and 12/15-LOX-mediated regulation of bioactive lipids during lung fungal infection and (2) to determine how the cellular source of IL-33 modulates bioactive lipid production and immunity during lung fungal infection.

曲霉菌是一种机会主义的模具，导致难以治疗侵入性真菌感染免疫功能低下和免疫抑制的个体，通常导致致命的结果。目的这种具有竞争性的更新R01是基于我们最近发现生物活性脂质角色的作品肺真菌感染期间免疫反应的介质患有烟曲霉。在上一个资金期间，我们提出了三个新颖的发现：（i）IL-33受体信号传导对17 烟曲霉感染期间的反应，（ii）eicosanoid PGE2正阳性调节IL-17A和IL-22诱导（3）IL-33受体信号对PGE2的负面调节（J Immunol 99：2140-2148，2017）。在其他该提案支持的工作，我们报告说12/15-脂氧酶（12/15-lox，Alox15 - / - ）的缺乏症导致炎症反应受损和对肺炎曲霉感染肺部感染的深刻敏感性（J Immunol 204：1849-1858，2020）。有趣的是，我们在Alox15 - / - 小鼠中观察到的敏感性机制是骨髓中嗜中性粒细胞的成熟受损。我们的发现总体上引起了一些有趣的问题：（i）IL-33在肺真菌感染期间如何调节PGE2？（ii）IL-33是否调节生产其他生物活性脂质？（iii）除PGE2以外的生物活性脂质可以调节感染期间的免疫反应与烟曲霉？（iv）是特定的生物活性脂质，或者是对中性粒细胞成熟或在感染？烟曲霉暴露小鼠的肺组织的脂质分析表明IL-33信号传导是多种生物活性脂质类别的深刻负面调节剂，包括前列腺素，羟基甲己己烯酸（HDHAS），羟基苯丙烯烯酸（HEPES）和羟基乙烯烯酸（HETES）。数据进一步显示Alox15 - / - 小鼠具有独特的肺脂质特征在烟曲霉感染期间，一种可能功能可调节中性粒细胞介导的对烟曲霉的免疫力。在其他研究中，采用IL33Flox/Flox-EGFP报告基因小鼠以及流式细胞仪和荧光的组合免疫组织化学，我们表明树突状细胞和中性粒细胞是IL-33的免疫细胞来源肺泡II细胞是烟曲霉感染期间肺中IL-33的主要非免疫细胞来源。最近的研究表明，IL-33（即髓样与上皮）的细胞来源可能具有巨大的作用关于免疫反应的类型。总体而言，我们的假设是由细胞因子（例如 IL-33和诸如12/15/-Lox的酶调节烟曲霉肺部感染期间的炎症反应。这该提案的具体目的是：（1）确定与IL-33和功能相关的机制和功能肺真菌感染期间的12/15-lox介导的生物活性脂质调节，（2）如何确定如何 IL-33的细胞来源调节肺真菌感染期间的生物活性脂质产生和免疫力。