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: 8662158
• 负责人: ANGELA HACZKU
• 金额: $ 39.59万
• 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/8662158
• 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; 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）：慢性心理社会应激改变了对各种感染性和炎症性疾病的易感性，并增强了哮喘气道反应。虽然下丘脑-垂体-肾上腺轴在应激过程中的激活早已被认识，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，过敏性气道炎症吸入过敏原的发展是通过调节气道树突状细胞功能的稳态机制，通过肺聚集蛋白，表面活性蛋白D（SP-D）。我们假设，皮质类固醇不敏感的髓样树突状细胞（由于细胞类型特异性损害GR表达和异常之间的相互作用的GR和NF-？B）介导应激对过敏性气道炎症的增强作用。改变的GR功能减弱了响应于变应原吸入的上皮细胞中SP-D合成的保护性升高。这种效应反过来又进一步放大树突状细胞和T细胞的活化，使气道炎症反应持续下去。目的1是确定如何在体内应激诱导的肺树突状细胞和T细胞的皮质类固醇不敏感性改变过敏性气道变化。使用GR激动剂、拮抗剂和CRH-/-小鼠组合社交破坏应激（SDR）和过敏性气道炎症，我们将检验社交应激诱导的过敏性气道炎症增强部分由皮质类固醇不敏感的树突细胞和/或T细胞介导的假设.通过调查GR和NF-？B表达和DNA结合皮质酮处理的树突状细胞和T细胞，我们将确定是否皮质类固醇不敏感需要GR下调和/或异常NF-？B-GR“系留”目的2将检验以下假设：应激减弱了响应于过敏原攻击的SP-D转录的增加，并且SP-D通过抑制髓样树突状细胞的分化和活化来保护免受Th 2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。使用条件性SP-D表达小鼠，我们将确定是否缺乏SP-D易患和SP-D过度表达保护对抗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和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，我们将检验CRD-SIRPa连接是SP-D的抑制作用所需的假设。阐明应激诱导的GR和SP-D调节受损的重要性具有很大的临床意义，因为可以设计潜在的新方法来控制肺中的过敏性免疫应答。

项目成果

Blomia tropicalis-Specific TCR Transgenic Th2 Cells Induce Inducible BALT and Severe Asthma in Mice by an IL-4/IL-13-Dependent Mechanism.

• DOI: 10.4049/jimmunol.1502676
• 发表时间: 2016-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chua YL;Liong KH;Huang CH;Wong HS;Zhou Q;Ler SS;Tang Y;Low CP;Koh HY;Kuo IC;Zhang Y;Wong WS;Peh HY;Lim HY;Ge MQ;Haczku A;Angeli V;MacAry PA;Chua KY;Kemeny DM
• 通讯作者: Kemeny DM

The Th2 gene cluster unraveled: role of RHS6.

揭示 Th2 基因簇：RHS6 的作用。

• DOI: 10.1111/all.13130
• 发表时间: 2017
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Flayer,CH;Haczku,A
• 通讯作者: Haczku,A

PARP-1: a new player in the asthma field?

PARP-1：哮喘领域的新参与者？

• DOI: 10.1111/j.1398-9995.2011.02551.x
• 发表时间: 2011
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Szabó,É;Kovács,I;Grune,T;Haczku,A;Virág,L
• 通讯作者: Virág,L

The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in Aspergillus fumigatus sensitized mice.

• DOI: 10.1186/1465-9921-13-100
• 发表时间: 2012-11-12
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Jiang Z;Fehrenbach ML;Ravaioli G;Kokalari B;Redai IG;Sheardown SA;Wilson S;Macphee C;Haczku A
• 通讯作者: Haczku A

Recent advances in alveolar biology: evolution and function of alveolar proteins.

• DOI: 10.1016/j.resp.2010.04.023
• 发表时间: 2010-08-31
• 期刊: RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
• 影响因子: 2.3
• 作者: Orgeig, Sandra;Hiemstra, Pieter S.;Veldhuizen, Edwin J. A.;Casals, Cristina;Clark, Howard W.;Haczku, Angela;Knudsen, Lars;Possmayer, Fred
• 通讯作者: Possmayer, Fred