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：
10316508
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/10316508
关键词：
Acids Alveolar Amplifiers Arachidonate 15-Lipoxygenase Arachidonate 5-Lipoxygenase Aspergillus fumigatus Asthma Attention Biological Biology Bone Marrow Cells Cellularity Chronic Obstructive Airway Disease Colitis Cytochrome P450 Data Dendritic Cells Development Dinoprost Dinoprostone Disease Eicosanoids Enzymes Epithelial Epithelial Cells Flow Cytometry Funding Generations Host Defense Human Hydroxyeicosatetraenoic Acids ITGAX gene Immune Immune response Immunity Immunocompromised Host Immunohistochemistry Impairment Individual Infection Inflammatory Inflammatory Response Interleukin-17 LOX gene Lipid III Lipids Lipoxygenase 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 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.

烟曲霉是一种机会性霉菌，会导致难以治疗的侵袭性真菌感染。免疫功能低下和免疫抑制的个体，通常会导致致命的结果。的目标这个竞争性更新 R01 是建立在我们最近的工作基础上的，该工作揭示了生物活性脂质的作用烟曲霉肺部真菌感染期间免疫反应的介质。在上一个资助期内，我们取得了三项新发现：(i) IL-33 受体信号传导负调节免疫保护性 17 型烟曲霉感染期间的反应，(ii) 类二十烷酸 PGE2 正向调节 IL-17A 和 IL-22 诱导 (3) IL-33 受体信号传导负向调节 PGE2 的产生 (JImmunol 99:2140-2148, 2017)。在其他方面在该提案支持的工作中，我们报告了 12/15-脂氧合酶（12/15-LOX、Alox15-/-）的缺乏导致炎症反应受损和对烟曲霉肺部感染的高度易感性（J 免疫学 204：1849-1858，2020）。有趣的是，我们在 Alox15-/- 小鼠中观察到的易感性机制是骨髓中的中性粒细胞成熟受损。总体而言，我们的发现引发了一些有趣的事情问题：(i) IL-33 在肺部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) PGE2 以外的生物活性脂质能否调节感染期间的免疫反应与烟曲霉？ (iv) 中性粒细胞成熟所需的特定生物活性脂质或负调节中性粒细胞成熟过程中的特定生物活性脂质感染？对暴露于烟曲霉的小鼠肺组织的脂质组学分析表明，IL-33 信号传导是多种生物活性脂质类别的深刻负调节剂，包括前列腺素，羟基二十二碳六烯酸 (HDHA)、羟基二十碳五烯酸 (HEPE) 和羟基二十碳四烯酸（HETE）。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，一种可能起到调节中性粒细胞介导的对烟曲霉免疫的作用。在其他研究中，使用 Il33flox/flox-eGFP 报告小鼠并结合流式细胞术和荧光免疫组织化学显示，树突状细胞和中性粒细胞是 IL-33 的免疫细胞来源，而烟曲霉感染期间，肺泡 II 型细胞是肺部 IL-33 的主要非免疫细胞来源。最近的研究表明 IL-33 的细胞来源（即骨髓细胞与上皮细胞）可能具有显着的影响关于免疫反应的类型。总的来说，我们的假设是生物活性脂质受细胞因子的调节，例如 IL-33 和 12/15/-LOX 等酶可调节烟曲霉肺部感染期间的炎症反应。这该提案的具体目标是：(1) 确定与 IL-33 相关的机制和功能肺部真菌感染期间 12/15-LOX 介导的生物活性脂质调节以及 (2) 确定如何 IL-33 的细胞来源可调节肺部真菌感染期间生物活性脂质的产生和免疫。