Serum Amyloid A3 in Allergic Asthma: An Endogenous Mediator of Disease Severity

过敏性哮喘中的血清淀粉样蛋白 A3：疾病严重程度的内源性介质

• 批准号: 8802887
• 负责人: Matthew E Poynter
• 金额: $ 37.55万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8802887
• 关键词: Acute; Address; Affect; Allergens; Allergic; Amyloid; Animal Model; Antibodies; Antigens; Asthma; Biological Markers; Biopsy; Breathing; CD4 Positive T Lymphocytes; Clinical; Dependence; Development; Disease; Epithelial; Epithelial Cells; Extrinsic asthma; Family; Gene Expression; Genes; Glucocorticoids; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunoglobulins; In Vitro; Inflammation Mediators; Interleukin-1; Interleukin-17; Irrigation; Knock-out; Knockout Mice; Lead; Leukocyte Chemotaxis; Lung; Measures; Mediating; Mediator of activation protein; Metaplasia; Molecular; Mucous body substance; Mus; Nature; Neutrophilia; Nose; Ovalbumin; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Production; Publishing; Pulmonary Inflammation; Reagent; Recombinants; Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Serum; Serum amyloid A protein; Severities; Severity of illness; Small Interfering RNA; Source; Sputum; Syndrome; T cell response; T-Lymphocyte; Testing; Toll-Like Receptor 2; Transgenic Mice; Transgenic Organisms; Western Blotting; Work; adaptive immunity; airway epithelium; airway hyperresponsiveness; allergic airway disease; antigen challenge; asthmatic; asthmatic patient; cytokine; extracellular; in vivo; insight; member; methacholine; mouse model; neutralizing antibody; novel; overexpression; prevent; receptor; response; therapeutic development

DESCRIPTION (provided by applicant): The allergic asthma phenotype is affected by CD4+ T helper cell-produced cytokines, with severe clinical asthma and mouse models of severe disease associated with IL-17 production, neutrophilia, and glucocorticoid resistance. We demonstrate that Serum Amyloid A (SAA), an endogenous mediator produced by the airway epithelium, induces innate immune cytokine production, neutrophilia, and polarizes Th17 responses to innocuous inhaled antigens. We have reported that SAA stimulates the extracellular Toll-Like Receptor 2 (TLR2) and the intracellular NOD-like receptor, Nlrp3, which are required for the secretion of IL-1¿, a Th17- polarizing cytokine. In addition, pharmacologic antagonism of the IL-1 receptor prevents IL-17 production in vitro and IL-1 receptor-deficient (IL-1R¿-/-) mice do not undergo Th17 polarization in response to SAA3-inducing exposures that promote allergic sensitization to ovalbumin or to combined administration of SAA and ovalbumin. Finally, SAA exacerbates allergen-induced airway hyper-responsiveness to methacholine and enhances airway neutrophilia in allergen sensitized and challenged mice. We hypothesize that pulmonary SAA (SAA3 in mice) is an epithelial-derived endogenous mediator of allergic asthma severity that functions to polarize IL-1-dependent Th17 responses that contribute to severe disease. In Specific Aim 1 we will determine quantitative and qualitative patterns of Saa3 expression and SAA3 production during the development of allergic asthma in mouse models of disease. In Specific Aim 2 we will establish the effects of SAA on the antigen-specific CD4+ T cell adaptive immune response in vitro and in vivo using wildtype and inducible airway epithelial SAA3-secreting mice. We will determine whether SAA3 promotes Th17 polarization, whether the receptors TLR2, Nlrp3, IL-1R¿, and FPR2 (Formyl Protein Receptor 2, which has been shown to induce leukocyte chemotaxis to SAA) are involved, whether the activity is directly upon T cells, and whether the effect of SAA3 is glucorticoid-sensitive. In Specific Aim 3 we will establish in vivo the necessity (using Saa3 silencing, SAA3 neutralization, and SAA3 knockout mice) and sufficiency (using SAA instillation and inducible SAA3- producing transgenic mice) of SAA3 for augmentation of allergic asthma severity, addressing mechanisms implicated from the previous specific aims by which SAA3 worsens lung physiologic and structural allergic asthma phenotypes, including glucocorticoid responsiveness. Understanding the effect of endogenous mediators on Th17-inducing responses in allergic asthma will provide unprecedented insight into the varied nature of the asthma syndrome and may provide novel targets for the development of therapeutics.

描述（由申请方提供）：过敏性哮喘表型受CD 4 + T辅助细胞产生的细胞因子的影响，具有严重的临床哮喘和与IL-17产生、嗜中性粒细胞和糖皮质激素抵抗相关的严重疾病的小鼠模型。我们证明，血清淀粉样蛋白A（SAA），由气道上皮细胞产生的内源性介质，诱导先天性免疫细胞因子的产生，嗜中性粒细胞，并极化的Th 17细胞对无害的吸入抗原的反应。 我们已经报道了SAA刺激细胞外Toll样受体2（TLR 2）和细胞内NOD样受体Nlrp 3，这是分泌IL-1 <$（Th 17极化细胞因子）所必需的。此外，IL-1受体的药理学拮抗作用阻止了体外IL-17的产生，IL-1受体缺陷（IL-1 R-/-）小鼠在对SAA 3诱导暴露（促进对卵清蛋白的过敏性致敏）或SAA和卵清蛋白联合给药的反应中不经历Th 17极化。 最后，SAA加剧过敏原诱导的气道对乙酰甲胆碱的高反应性，并增强过敏原致敏和激发小鼠的气道嗜中性粒细胞。我们假设肺SAA（小鼠SAA 3）是过敏性哮喘严重程度的上皮源性内源性介质，其功能是抑制IL-1依赖性Th 17应答，导致严重疾病。在具体目标1中，我们将确定在小鼠疾病模型中过敏性哮喘发展过程中Saa 3表达和SAA 3产生的定量和定性模式。在特定目标2中，我们将使用野生型和诱导型气道上皮SAA 3分泌小鼠在体外和体内建立SAA对抗原特异性CD 4 + T细胞适应性免疫应答的影响。我们将确定SAA 3是否促进Th 17极化，是否涉及受体TLR 2，Nlrp 3，IL-1 R？和FPR 2（甲酰蛋白受体2，已被证明可诱导白细胞对SAA的趋化性），活性是否直接作用于T细胞，以及SAA 3的作用是否对糖皮质激素敏感。在具体目标3中，我们将在体内确定（使用Saa 3沉默、SAA 3中和和SAA 3敲除小鼠）和充分性（使用SAA滴注和可诱导的产生SAA 3的转基因小鼠）来增加过敏性哮喘的严重程度，解决了与先前的特定目的有关的机制，通过这些特定目的，SAA 3改变肺生理和结构过敏性哮喘表型，包括糖皮质激素反应性。 了解内源性介质对过敏性哮喘中Th 17诱导反应的影响，将为哮喘综合征的不同性质提供前所未有的见解，并可能为治疗方法的开发提供新的靶点。

项目成果

Serum amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4(+) T cells.

• DOI: 10.1038/cddis.2013.327
• 发表时间: 2013-09-05
• 期刊: Cell death & disease
• 影响因子: 9

Mitochondria-targeted drugs enhance Nlrp3 inflammasome-dependent IL-1β secretion in association with alterations in cellular redox and energy status.

• DOI: 10.1016/j.freeradbiomed.2013.01.025
• 发表时间: 2013-07
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Jabaut, Joshua;Ather, Jennifer L.;Taracanova, Alexandra;Poynter, Matthew E.;Ckless, Karina
• 通讯作者: Ckless, Karina

Immunological characteristics and management considerations in obese patients with asthma.

• DOI: 10.1586/1744666x.2015.1040394
• 发表时间: 2015
• 期刊: Expert review of clinical immunology
• 影响因子: 4.4
• 作者: Ather JL;Poynter ME;Dixon AE
• 通讯作者: Dixon AE