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: 8475423
• 负责人: ANGELA HACZKU
• 金额: $ 37.25万
• 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/8475423
• 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.

描述(由申请人提供)：慢性心理社会压力改变了对各种感染性和炎症性疾病的易感性，并增强了哮喘的呼吸道反应。虽然人们很早就认识到应激时下丘脑-垂体-肾上腺轴的激活，但内源性糖皮质激素在调节肺免疫反应中的作用仍不清楚。我们的初步研究表明，吸入变应原后过敏性呼吸道炎症的发展受到通过肺集合素、表面活性蛋白D(SP-D)调节气道树突状细胞功能的动态平衡机制的保护。我们推测，髓系树突状细胞对糖皮质激素的不敏感(由于细胞类型特异性的GR表达受损和GR与NF-β之间的异常相互作用)介导了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中SP-D合成的保护性升高，以应对过敏原吸入。这种效应反过来进一步放大树突状细胞和T细胞的激活，使炎症的呼吸道反应永久化。目的1确定应激诱导的肺树突状细胞和T细胞对糖皮质激素不敏感如何改变体内过敏性呼吸道的变化。使用GR激动剂、拮抗剂和CRH-/-小鼠，在社会破坏应激(SDR)和过敏性气道炎症的组合中，我们将检验这一假说，即社会应激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状细胞和/或T细胞介导的。通过研究皮质酮处理的树突状细胞和T细胞中GR和NF-B的表达和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-B-GR“拴系”。目的2将验证应激减弱SP-D转录增加以应对变应原攻击的假设，以及SP-D通过抑制髓系树突状细胞的分化和激活而防止Th2型炎症的发展的假设。通过研究肺泡II型上皮细胞中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改变是否影响SP-D的转录。使用条件性SP-D表达的小鼠，我们将确定是否缺乏SP-D易患过敏性呼吸道反应，而SP-D过度表达可保护应激诱导的过敏性呼吸道反应增强。通过研究含有糖识别(CRD)但不含胶原结构域的重组突变体SP-D对抗原提呈和Th细胞功能的影响，以及阻断针对负信号调节蛋白(SIRP)的抗体对SP-D抑制作用的影响，我们将检验这一假说。阐明应激诱导的GR和SP-D调节受损的重要性具有重要的临床意义，因为可以设计出潜在的新方法来控制肺内的过敏性免疫反应。