The role of ovarian hormones on allergen-mediatedd innate immune airway responses

卵巢激素对过敏原介导的先天免疫气道反应的作用

• 批准号: 9252844
• 负责人: Dawn C Newcomb
• 金额: $ 16万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252844
• 关键词: Affect; Allergens; Allergic; Alternaria; Antigens; Asthma; Automobile Driving; B-Lymphocytes; Basic Science; Bone Marrow; CD4 Positive T Lymphocytes; Cell Separation; Cell Surface Receptors; Cell surface; Cells; Child; Data; Enzyme-Linked Immunosorbent Assay; Estradiol; Exposure to; Female; Flow Cytometry; Future; GATA3 gene; Goals; Gonadal Steroid Hormones; Harvest; Histocytochemistry; Hormones; Immune; Immune response; Inbred BALB C Mice; Infiltration; Interleukin-13; Interleukin-5; Life; Liquid substance; Lung; Lymphoid Cell; Mediating; Menopause; Metaplasia; Mucous body substance; Mus; Ovarian hormone; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Periodic acid Schiff stain method; Phase; Plethysmography; Prevalence; Production; Progesterone; Protein Secretion; Protocols documentation; Puberty; Research; Role; Sex Characteristics; Staining method; Stains; Stimulus; Strategic Planning; Surface; T-Lymphocyte; TSLP gene; Testing; Testosterone; Time; United States National Institutes of Health; Woman; Women' s Health; adaptive immunity; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; base; boys; cytokine; eosinophil; fungus; gender disparity; girls; mRNA Expression; macrophage; male; men; microbial; middle age; operation; protein expression; public health relevance; receptor; response; therapeutic target

 DESCRIPTION (provided by applicant): Asthma prevalence is greater in boys than girls, but around puberty there is a shift in asthma prevalence, and at mid-life women are about two times more likely than men to have asthma. This suggests a role for sex hormones in asthma pathogenesis; however the mechanisms remain unknown. Group 2 innate lymphoid cells (ILC2) are important in driving the initial phase of allergic airway inflammation that is associated with asthma. ILC2 are activated by IL-33, TSLP, and IL-25 which are upregulated in response to airway allergens, including Alternaria alternata. Upon stimulation, ILC2 have increased expression of the transcription factors GATA3 and RORα and produce IL-5 and IL-13. IL-5 and IL-13 increase the infiltration of eosinophils, airway hyperresponsiveness (AHR), and mucus production, all hallmarks of asthma. Our preliminary data showed IL- 33-stimulated ILC2 from female mice had significantly increased IL-5 and IL-13 protein expression compared to ILC2 from male mice. Therefore, we hypothesize that the ovarian hormones, 17beta-estradiol (17β-E2) and progesterone (P4), increase ILC2-induced airway inflammation. In Aim 1 we will determine the mechanisms by which sex hormones increase IL-5 and IL-13 production from ILC2. Sham-operated female and male mice, ovariectomized female mice, and orchidectomized male mice will be administered pellets containing vehicle, 17β-E2, P4, and/or testosterone. ILCs will be harvested from the bone marrow and lungs of these mice and stimulated with IL-33 ex vivo. IL-5 and IL-13 protein expression, RORα and GATA3 mRNA expression, and surface expression of ST2, a component of the IL-33 receptor, will then be determined in ILC2. In Aim 2, we will determine the role of ovarian hormones on Alternaria extract (Alt Ex)-induced innate immune-mediated airway inflammation. WT BALB/c female, male, ovariectomized, and orchidectomized mice will be challenged with Alt Ex for 4 days to initiate an innate immune response. We will then determine ILC2 cytokine expression, airway inflammation, AHR, and mucus production. This proposal will delineate a mechanism(s) by which sex hormones regulate ILC2, and it may identify potential therapeutic targets for patients, in particular women, with asthma.

 描述（由申请人提供）：男孩的哮喘患病率高于女孩，但在青春期左右，哮喘患病率发生变化，中年女性患哮喘的可能性约为男性的两倍。这表明性激素在哮喘发病机制中发挥作用;但其机制仍不清楚。第2组先天性淋巴样细胞（ILC 2）在驱动与哮喘相关的过敏性气道炎症的初始阶段中是重要的。ILC 2被IL-33、TSLP和IL-25激活，IL-33、TSLP和IL-25响应于气道变应原（包括链格孢菌）而上调。在刺激后，ILC 2增加了转录因子GATA 3和RORα的表达，并产生IL-5和IL-13。IL-5和IL-13增加嗜酸性粒细胞的浸润、气道高反应性（AHR）和粘液产生，所有这些都是哮喘的标志。我们的初步数据显示，与来自雄性小鼠的ILC 2相比，来自雌性小鼠的IL- 33刺激的ILC 2具有显著增加的IL-5和IL-13蛋白表达。因此，我们假设卵巢激素17 β-雌二醇（17β-E2）和孕酮（P4）增加了ILC 2诱导的气道炎症。在目标1中，我们将确定性激素增加ILC 2产生IL-5和IL-13的机制。将对假手术雌性和雄性小鼠、卵巢切除雌性小鼠和去势雄性小鼠给予含有溶媒、17β-E2、P4和/或睾酮的丸剂。将从这些小鼠的骨髓和肺收获ILC，并用IL-33离体刺激。然后在ILC 2中测定IL-5和IL-13蛋白表达、RORα和GATA 3 mRNA表达以及ST 2（IL-33受体的一种组分）的表面表达。在目的2中，我们将确定卵巢激素对链格孢属提取物（Alt Ex）诱导的先天免疫介导的气道炎症的作用。WT BALB/c雌性、雄性、卵巢切除和卵巢切除小鼠将用Alt Ex攻击4天以引发先天免疫应答。然后我们将确定ILC 2细胞因子表达，气道炎症，AHR和粘液产生。这项提案将阐明性激素调节ILC 2的机制，并可能为哮喘患者，特别是女性患者确定潜在的治疗靶点。