Biology of innate IL-22 during lung fungal infection

烟曲霉是一种机会主义的霉菌，在中国造成难以治疗的侵袭性真菌感染。 免疫受损和免疫抑制的个体，通常导致致命的结果。的目标是 这一竞争性更新R01是建立在我们最近的工作基础上的，这些工作揭示了生物活性脂质的作用 肺部真菌感染烟曲霉菌时免疫反应的介体。在上一次筹资期间， 我们有三个新的发现：(I)IL-33受体信号负性调节免疫保护型17 烟曲霉菌感染过程中的反应：(Ii)二十烷类前列腺素E_2正向调节IL-17A和IL-22的诱导 (3)IL-33受体信号负性调节PGE2的产生(J免疫99：2140-2148,2017)。在其他 在这项提议的支持下，我们报告了12/15-脂氧合酶(12/15-LOX，ALOX15-/-)缺陷 导致炎症反应受损，对烟曲霉菌肺部感染高度敏感(J 免疫学204：1849-1858,2020)。有趣的是，我们在ALOX15-/-小鼠身上观察到的易感机制是 骨髓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 问题：(I)在肺部真菌感染过程中，IL-33如何调节PGE2？(Ii)IL-33是否调节生产 其他生物活性脂类？(Iii)PGE2以外的生物活性脂类能否调节感染期间的免疫反应 和烟曲霉菌一起？(Iv)在中性粒细胞成熟过程中，是否需要或负向调节中性粒细胞成熟所需的特定生物活性脂质？ 感染？烟曲霉菌暴露小鼠肺组织的脂质组学分析表明IL-33信号转导 是多种生物活性脂类的深层负性调节因子，包括前列腺素， 羟基二十二碳六烯酸(HDHAs)、羟基二十碳五烯酸(HEPES)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特征 在烟曲霉菌感染过程中，一种可能调节中性粒细胞介导的对烟曲霉菌免疫的分子。 在其他研究中，使用了Il33Flox/FLOX-EGFP报告小鼠以及流式细胞术和荧光技术的组合 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 在烟曲霉菌感染过程中，肺泡II型细胞是肺部产生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(即髓系与上皮性)可能有戏剧性的影响 关于免疫反应的类型。总体而言，我们的假设是生物活性脂质，由细胞因子调节，如 IL-33和12/15/-LOX等酶可调节烟雾假单胞菌肺部感染时的炎症反应。这个 本提案的具体目的是：(1)确定与IL-33和IL-33相关的机制(S)和功能 12/15-LOX介导的肺部真菌感染期间生物活性脂质的调节以及(2)确定 IL-33的细胞来源在肺部真菌感染时调节生物活性脂质的产生和免疫。

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.