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

描述（由申请人提供）：慢性社会心理压力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。虽然下丘脑-垂体-肾上腺轴在应激时的激活早已被认识到，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，吸入过敏原后过敏性气道炎症的发生受到稳态机制的保护，该机制通过肺集合、表面活性剂蛋白D （SP-D）调节气道树突状细胞功能。我们假设髓系树突状细胞的皮质类固醇不敏感(由于细胞类型特异性的GR表达损伤和GR与NF-？B)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中SP-D合成的保护性提高，这是对过敏原吸入的反应。这种效应反过来又进一步放大树突细胞和T细胞的激活，使气道炎症反应永久化。目的1是确定应激诱导的肺树突状细胞和T细胞的皮质类固醇不敏感如何改变体内过敏性气道的变化。使用GR激动剂、拮抗剂和CRH-/-小鼠，结合社会中断应激（SDR）和过敏性气道炎症，我们将检验社会应激诱导的过敏性气道炎症增强部分是由皮质类固醇不敏感的树突状细胞和/或T细胞介导的假设。通过研究GR和NF-？在皮质酮处理的树突状细胞和T细胞中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NF-？B-GR“拘束”。目的2将验证以下假设：应激会减弱SP-D转录的增加，以应对过敏原的挑战；SP-D通过抑制骨髓树突状细胞的分化和激活来保护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会影响SP-D转录。使用条件SP-D表达小鼠，我们将确定缺乏SP-D是否易于和SP-D过表达是否可以防止应激诱导的过敏性气道反应增强。通过研究含有碳水化合物识别（CRD）但不含胶原结构域的重组突变体SP-D，并阻断针对负信号调节蛋白（SIRP）的抗体对抗原提呈和Th细胞功能的影响，我们将验证CRD- sirpa连接是SP-D抑制作用所必需的假设。阐明应激诱导的GR和SP-D调节损伤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部的过敏性免疫反应。

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.