Mechanisms of social-stress enhanced allergic airway response in a mouse model

社会压力增强小鼠模型过敏性气道反应的机制

• 批准号: 8084157
• 负责人: ANGELA HACZKU
• 金额: $ 40.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084157
• 关键词: Address; Adoptive Transfer; Adrenal Cortex Hormones; Affect; Agonist; Air; Allergens; Allergic; Alveolar; Antigens; Asthma; Attenuated; Binding; Biological Response Modifiers; Blocking Antibodies; Bone Marrow; Breathing; CCAAT-Enhancer-Binding Proteins; CCL17 gene; CRH gene; Carbohydrates; Cell Differentiation process; Cell physiology; Cells; Chronic; Collagen; Collectins; Corticosterone; DNA Binding; Data; Dendritic Cells; Development; Disease; Distal; EMSA; Eotaxin; Epithelial Cells; Exposure to; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Homeostasis; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Ligation; Lung; Mediating; Molecular; Mus; Myelogenous; NF-kappa B; Pathway interactions; Predisposition; Process; Production; Psychological Stress; Psychosocial Stress; Pulmonary Surfactant-Associated Protein D; Recombinants; Regulation; Role; SHPS-1 protein; STAT3 gene; Splenocyte; Steroids; Stress; Structure of parenchyma of lung; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Tissues; Validation; airway inflammation; allergic airway inflammation; asthmatic airway; cell type; clinically relevant; hypothalamic-pituitary-adrenal axis; in vivo; migration; mouse model; mutant; novel strategies; prevent; public health relevance; receptor downregulation; receptor expression; receptor function; response; social; social stress; transcription factor

DESCRIPTION (provided by applicant): Chronic psychosocial stress alters susceptibility to various infectious and inflammatory disorders and enhances the asthmatic airway response. Although hypothalamic-pituitary-adrenal axis activation during stress has long been recognized, the role of endogenous glucocorticoids in regulating the pulmonary immune response remains unclear. Our preliminary studies showed that development of allergic airway inflammation upon inhalation of allergen is protected by homeostatic mechanisms modulating airway dendritic cell function through the lung collectin, surfactant protein D (SP-D). We hypothesize that corticosteroid insensitivity of myeloid dendritic cells (due to cell-type specific impairment of GR expression and abnormal interactions between the GR and NF-?B) mediate the enhancing effects of stress on allergic airway inflammation. Altered GR function attenuates the protective raise in SP-D synthesis in epithelial cells, in response to allergen inhalation. This effect in turn further amplifies dendritic and T cell activation, perpetuating the inflammatory airway response. Aim 1 is to define how stress-induced corticosteroid insensitivity in lung dendritic cells and T cells alter the allergic airway changes in vivo. Using GR agonists, antagonists and CRH-/- mice in a combination of social disruption stress (SDR) and allergic airway inflammation we will test the hypothesis that social stress- induced enhancement of allergic airway inflammation is in part, mediated by corticosteroid insensitive dendritic and/or T cells. By investigating GR and NF-?B expression and DNA binding in corticosterone treated dendritic and T cells, we will define whether corticosteroid insensitivity requires GR downregulation and/or an abnormal NF-?B-GR "tethering". Aim 2 will test the hypotheses that stress attenuates the increase in SP-D transcription in response to allergen challenge and that SP-D protects against development of Th2- type inflammation by inhibiting differentiation and activation of myeloid dendritic cells. By investigating GR, C/EBP and STAT interactions in type II alveolar epithelial cells, we will determine whether stress-induced changes in corticosteroid function affect SP-D transcription. Using conditional SP-D expressor mice we will define if lack of SP-D predisposes to and SP-D over expression protects against the stress-induced enhancement of the allergic airway response. By studying the effects of a recombinant mutant SP-D containing the carbohydrate recognition (CRD), but not the collagen domain, and blocking antibodies against the negative Signal-Regulatory Protein (SIRP) on antigen presenting and Th cell function, we will test the hypothesis that CRD-SIRPa ligation is required for the inhibitory effects of SP-D. Elucidation of the importance of stress-induced impairment of GR and SP-D regulation has great clinical relevance since potentially novel approaches can be devised to control the allergic immune response in the lung. PUBLIC HEALTH RELEVANCE: Psychosocial stress has severe impact on the course of chronic asthma but the mechanisms are poorly defined. The broad objectives of this project are: 1. Validation of the importance of altered glucocorticoid responsiveness by immune cells and surfactant protein D (SP-D) expression and function in the impact of psychosocial stress on allergic airway inflammation. 2. Elucidation of the cellular and molecular pathways of the glucocorticoid action on immune cell function and epithelial cell SP-D production in stress-induced exacerbation of the inflammatory airway response.

描述（由申请人提供）：慢性社会心理压力会改变对各种感染性和炎症性疾病的易感性，并增强哮喘气道反应。尽管人们早已认识到应激期间下丘脑-垂体-肾上腺轴的激活，但内源性糖皮质激素在调节肺部免疫反应中的作用仍不清楚。我们的初步研究表明，吸入过敏原后过敏性气道炎症的发展受到通过肺集合素、表面活性蛋白 D (SP-D) 调节气道树突细胞功能的稳态机制的保护。我们假设骨髓树突状细胞的皮质类固醇不敏感性（由于GR表达的细胞类型特异性损伤以及GR和NF-κB之间的异常相互作用）介导应激对过敏性气道炎症的增强作用。 GR 功能的改变减弱了上皮细胞响应过敏原吸入而产生的保护性 SP-D 合成。这种效应反过来又进一步放大树突状细胞和 T 细胞的激活，使炎症气道反应持续下去。目标 1 是确定肺树突状细胞和 T 细胞中压力诱导的皮质类固醇不敏感如何改变体内过敏性气道变化。使用 GR 激动剂、拮抗剂和 CRH-/- 小鼠，结合社会破坏应激 (SDR) 和过敏性气道炎症，我们将检验以下假设：社会压力诱导的过敏性气道炎症的增强部分是由皮质类固醇不敏感的树突和/或T细胞。通过研究皮质酮处理的树突状细胞和 T 细胞中 GR 和 NF-κB 的表达以及 DNA 结合，我们将确定皮质类固醇不敏感是否需要 GR 下调和/或异常的 NF-κB-GR“束缚”。目标 2 将检验以下假设：应激会减弱响应过敏原挑战的 SP-D 转录增加，以及 SP-D 通过抑制骨髓树突状细胞的分化和活化来防止 Th2 型炎症的发展。通过研究 II 型肺泡上皮细胞中 GR、C/EBP 和 STAT 的相互作用，我们将确定应激诱导的皮质类固醇功能变化是否影响 SP-D 转录。使用有条件的 SP-D 表达小鼠，我们将确定 SP-D 缺乏是否会导致过敏性气道反应，而 SP-D 过度表达是否会防止应激引起的过敏性气道反应增强。通过研究含有碳水化合物识别 (CRD) 但不含有胶原结构域的重组突变体 SP-D 以及针对负信号调节蛋白 (SIRP) 的阻断抗体对抗原呈递和 Th 细胞功能的影响，我们将测试假设SP-D的抑制作用需要CRD-SIRPa连接。阐明应激引起的 GR 和 SP-D 调节受损的重要性具有很大的临床意义，因为可以设计出潜在的新方法来控制肺部的过敏性免疫反应。 公共卫生相关性：社会心理压力对慢性哮喘病程有严重影响，但其机制尚不清楚。该项目的主要目标是： 1. 验证免疫细胞和表面活性蛋白 D (SP-D) 表达和功能改变的糖皮质激素反应性在心理社会压力对过敏性气道炎症影响中的重要性。 2. 阐明糖皮质激素在应激诱导的炎症气道反应加剧过程中对免疫细胞功能和上皮细胞 SP-D 产生的作用的细胞和分子途径。