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: 8274810
• 负责人: ANGELA HACZKU
• 金额: $ 39.91万
• 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/8274810
• 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）：慢性社会心理压力改变了对各种感染和炎症性疾病的敏感性，并增强了哮喘性气道反应。尽管长期以来已经识别出下丘脑 - 垂体 - 肾上腺轴激活，但内源性糖皮质激素在调节肺免疫反应中的作用尚不清楚。我们的初步研究表明，吸入过敏原后过敏性气道炎症的发育受到通过肺部收集蛋白，表面活性剂蛋白D（SP-D）调节气道树突状细胞功能的稳态机制的保护。我们假设髓样树突状细胞的皮质类固醇不敏感性（由于细胞类型的特异性损害GR表达以及GR和NF-- b之间的异常相互作用）介导了压力对过敏性气道炎症的增强作用。改变的GR功能会减弱上皮细胞中SP-D合成中的保护性升高，以响应过敏原吸入。反过来，这种作用进一步扩大了树突状和T细胞的激活，从而使炎症气道反应永存。目的1是定义肺树突状细胞和T细胞中压力诱导的皮质固醇不敏感性如何改变体内过敏性气道变化。使用GR激动剂，拮抗剂和CRH - / - 小鼠在社会干扰应力（SDR）和过敏性气道炎症的结合中，我们将检验以下假设：社会胁迫诱导的过敏性气道炎症的增强是部分介导的，是由皮质类固醇激素不敏感的树突不敏感的树突状和/或T细胞介导的。通过研究经皮质酮处理的树突状和T细胞中的GR和NF-？B表达和DNA结合，我们将定义皮质类固醇不敏感性是否需要GR下调和/或异常的NF-？B？B-Gr“ Tethering”。 AIM 2将测试压力响应过敏原挑战时压力减弱SP-D转录增加的假设，并且SP-D通过抑制分化和激活髓样树突状细胞来防止Th2-型炎症的发展。通过研究II型肺泡上皮细胞中的GR，C/EBP和Stat相互作用，我们将确定应激诱导的皮质类固醇功能的变化是否影响SP-D转录。使用条件的SP-D表达小鼠，我们将定义是否缺乏SP-D易感性，而SP-D超过表达可以防止应力诱导的过敏气道反应增强。通过研究含有碳水化合物识别（CRD）的重组突变体SP-D的影响，但不是胶原蛋白结构域，并阻止针对阴性信号调节蛋白（SIRP）对抗原呈现和TH细胞功能的抗体，我们将测试CRD-SIRPA连接的假设是SP-D的抑制作用。阐明应力诱导的GR和SP-D调节损伤的重要性具有很大的临床相关性，因为可以设计潜在的新方法来控制肺中的过敏性免疫反应。 公共卫生相关性：社会心理压力对慢性哮喘的进程有严重影响，但定义很差。该项目的广泛目标是：1。验证免疫细胞和表面活性剂蛋白D（SP-D）（SP-D）表达和功能对社会心理应激对过敏性气道炎症的影响的重要性。 2。在应激引起的炎症性气道反应加剧中，糖皮质激素作用对免疫细胞功能和上皮细胞SP-D产生的细胞和分子途径阐明。