The Role of IL-17 in fungal keratitis

IL-17在真菌性角膜炎中的作用

• 批准号: 8521211
• 负责人: Patricia R Taylor
• 金额: $ 5.39万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521211
• 关键词: Adoptive Transfer; Antifungal Agents; Aspergillus; Biological Assay; Blindness; Bone Marrow; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cells; Cornea; Corneal Diseases; Corneal Opacity; Corneal Stroma; Corneal Ulcer; Data; Development; Disease; EMSA; Flow Cytometry; Fusarium; Hyphae; IL8RB gene; Immune response; Immunity; Immunization; In Vitro; Incubated; Infection; Interferons; Interleukin-16; Interleukin-17; Interleukin-6; Keratitis; Lead; Manuscripts; Mediating; Messenger RNA; Modeling; Mus; Mycoses; Nuclear Extract; Phenotype; Population; Production; Promoter Regions; RNA; Reactive Oxygen Species; Recombinants; Recruitment Activity; Regulation; Relative (related person); Role; Route; STAT3 gene; Sorting - Cell Movement; Source; Spleen; Splenocyte; Th1 Cells; Time; Transcript; Visual impairment; Western Blotting; abstracting; adaptive immunity; cell type; chemokine; interleukin-23; killings; mRNA Expression; magnetic beads; neutralizing antibody; neutrophil; novel; research study; subcutaneous

DESCRIPTION (provided by applicant): IL-17 and Th17 cells have an important role in the host response to fungal infections. In the current study, we examined the role of IL-17 in a murine model of Aspergillus and Fusarium infections of the cornea, which are a major cause of blindness and visual impairment worldwide. C57BL/6 mice immunized by intratracheal or subcutaneous routes. Mice immunized by either route demonstrated rapid fungal clearance and significantly reduced corneal disease compared with unimmunized, infected mice which severe corneal opacity and a persistent fungal presence. Intracellular flow cytometry showed development of fungal-specific Th1 and Th17 cells in the spleen following immunization, which were selectively recruited to the cornea after infection (Th17 cells at 48h, and Th1 cells at 72h). Neutralization of IL-17 following immunization, or infection of IL-17-/- mice inhibited the protective phenotype, whereas IFN-? neutralization had no effect. A discrete population of IL-17 producing neutrophils was detected in the corneas 24h after infection corneas of immunized, but not unimmunized mice, and were detected in the spleen and bone marrow. Further, neutrophil depletion impaired IL-17 production at this time and blocked protective immunity. IL-17 producing neutrophils produced elevated ROS and had increased capacity to kill hyphae in vitro, indicating that this population of cells has an important role in regulating fungal infectio. Quantitative PCR of the FACS sorted IL-17 neutrophils from the cornea, spleen and bone marrow showed IL-17 transcripts, indicating de novo synthesis. Further, naive bone marrow neutrophils expressed IL-17 RNA when incubated with splenocyte supernatants from immunized mice, and expression was ablated in the presence of both anti-IL-6 and anti-IL-23. Conversely, stimulation with both IL-16 and IL-23, but not with single Abs stimulated IL-17 expression. Together, these data indicate that IL-17 producing neutrophils are generated by IL-6 and IL-23 in immunized mice, and are recruited to fungal infected corneas, resulting in rapid fungal clearance possibly due to elevated production of reactive oxygen species or interactions with Th17 cells. These findings show a role for IL-17, Th17, and IL-17 producing neutrophils in regulating fungal infections. In the proposed experiments I will determine the relative contribution of Th17 cells and IL-17 producing cells in protective immunity in fungal keratitis. )

描述（由申请人提供）：IL-17和Th17细胞在宿主对真菌感染的反应中起重要作用。在目前的研究中，我们研究了IL-17在小鼠角膜曲霉菌和镰刀菌感染模型中的作用，这是全世界失明和视力障碍的主要原因。C57BL/6小鼠经气管内或皮下免疫。与未免疫、角膜混浊严重且真菌持续存在的感染小鼠相比，通过这两种途径免疫的小鼠表现出快速的真菌清除和显著减少角膜疾病。细胞内流式细胞术显示，免疫后脾脏中出现了真菌特异性Th1和Th17细胞，这些细胞在感染后被选择性地募集到角膜中（48小时的Th17细胞，72小时的Th1细胞）。