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
• 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
• 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/10474632
• 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; 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

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.

烟曲霉菌是一种机会性霉菌，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，通常导致致命的结果。的目标 这一竞争性更新R 01是建立在我们最近的工作，已经发现的作用，生物活性脂质 介导的免疫反应在肺部真菌感染A.烟熏。在上一个供资期间， 我们有三个新的发现：（i）IL-33受体信号负调节免疫保护型17 反应在A。烟曲霉感染，（ii）类花生酸PGE 2正调节IL-17 A和IL-22诱导 和（3）IL-33受体信号负调节PGE 2产生（J Immunol 99：2140-2148，2017）。换句 在这项工作的支持下，我们报道了12/15-脂氧合酶（12/15-LOX，Alox 15-/-） 导致炎症反应受损和对A.烟曲霉 Immunol 204：1849-1858，2020）。有趣的是，我们在Alox 15-/-小鼠中观察到的易感性机制是 骨髓中中性粒细胞成熟受损。我们的研究结果总体上引发了一些有趣的 问题：（i）IL-33在肺部真菌感染期间如何调节PGE 2？(ii)IL-33是否调节 其他生物活性脂质的含量(iii)除了PGE 2以外的生物活性脂质是否可以在感染期间调节免疫应答 名为.烟熏？(iv)是中性粒细胞成熟过程中所需的或负调节中性粒细胞成熟的特定生物活性脂质， 感染？来自A.暴露于烟曲霉菌的小鼠证明IL-33信号传导 是多种生物活性脂质类的重要负调节剂，包括胰高血糖素， 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Alox 15-/-小鼠具有独特的肺脂质特征 在A. fumigatus感染，一种可能起调节嗜热链球菌介导的对A.烟熏。 在其他研究中，使用Il 33 flox/EIP-eGFP报告小鼠和流式细胞术和荧光免疫分析的组合， 免疫组化显示，树突状细胞和中性粒细胞是IL-33的免疫细胞来源， 肺泡II型细胞是A.烟曲霉感染 最近的研究表明，IL-33的细胞来源（即髓样与上皮细胞）可能具有显著的作用， 免疫反应的类型。总的来说，我们的假设是，生物活性脂质，由细胞因子， IL-33和酶如12/15/-LOX调节A.烟曲霉肺部感染的 该提案的具体目标是：（1）确定与IL-33相关的机制和功能， 肺真菌感染期间12/15-LOX介导的生物活性脂质的调节和（2）确定 IL-33的细胞来源调节肺真菌感染期间生物活性脂质的产生和免疫。