Cellular and molecular mechanisms of mucosal organ crosstalk in allergic diseases

过敏性疾病中粘膜器官串扰的细胞和分子机制

• 批准号: 10615150
• 负责人: Lisa Ann Spencer
• 金额: $ 47.03万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615150
• 关键词: Adaptor Signaling Protein; Adhesives; Adoptive Transfer; Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Anatomy; Antigens; Asthma; Biological Assay; Biological Markers; Blood Vessels; CCL11 gene; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Coculture Techniques; Data; Deposition; Detection; Development; Diagnostic; Distant; Dose; Economic Burden; Environment; Extrinsic asthma; Food Hypersensitivity; Frequencies; Generations; Genes; Health; Homeostasis; Homing; Hour; Human; IL5RA gene; ITGAM gene; Immune; Immune response; Immunity; Immunologics; In Vitro; Individual; Inflammatory; Inflammatory Response; Ingestion; Inhalation; Integrins; Interleukin-13; Interleukin-5; Intervention; Intestines; Intrinsic factor; Knowledge; Lung; Lymphoid Cell; Mediating; Mediator; Metaplasia; Molecular; Mouse Strains; Mucous Membrane; Mucous body substance; Mus; Natural History; Oral; Organ; Ovalbumin; Patients; Persons; Phenotype; Predisposition; Prevalence; Process; Pyroglyphidae; Reporter; Risk Factors; Role; Serum; Serum Proteins; Signal Transduction; Site; Skin; Standard Model; Stomach; Structure of parenchyma of lung; Surface; T-Lymphocyte; TSLP gene; Testing; Therapeutic; Tissues; Up-Regulation; Wild Type Mouse; cytokine; eosinophil; eosinophilic inflammation; extracellular vesicles; gene induction; genetic signature; gut-lung axis; in vivo; innovation; insight; migration; mouse model; nanoflow cytometry; nanoparticle; neutralizing antibody; novel; receptor; recruit; response; transcriptome; translational approach; Adaptor Signaling Protein; Adhesives; Adoptive Transfer; Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Anatomy; Antigens; Asthma; Biological Assay; Biological Markers; Blood Vessels; CCL11 gene; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Coculture Techniques; Data; Deposition; Detection; Development; Diagnostic; Distant; Dose; Economic Burden; Environment; Extrinsic asthma; Food Hypersensitivity; Frequencies; Generations; Genes; Health; Homeostasis; Homing; Hour; Human; IL5RA gene; ITGAM gene; Immune; Immune response; Immunity; Immunologics; In Vitro; Individual; Inflammatory; Inflammatory Response; Ingestion; Inhalation; Integrins; Interleukin-13; Interleukin-5; Intervention; Intestines; Intrinsic factor; Knowledge; Lung; Lymphoid Cell; Mediating; Mediator; Metaplasia; Molecular; Mouse Strains; Mucous Membrane; Mucous body substance; Mus; Natural History; Oral; Organ; Ovalbumin; Patients; Persons; Phenotype; Predisposition; Prevalence; Process; Pyroglyphidae; Reporter; Risk Factors; Role; Serum; Serum Proteins; Signal Transduction; Site; Skin; Standard Model; Stomach; Structure of parenchyma of lung; Surface; T-Lymphocyte; TSLP gene; Testing; Therapeutic; Tissues; Up-Regulation; Wild Type Mouse; cytokine; eosinophil; eosinophilic inflammation; extracellular vesicles; gene induction; genetic signature; gut-lung axis; in vivo; innovation; insight; migration; mouse model; nanoflow cytometry; nanoparticle; neutralizing antibody; novel; receptor; recruit; response; transcriptome; translational approach

Abstract Allergic diseases including food allergies and allergic asthma represent a substantial health and economic burden, with the US Centers for Disease Control (CDC) estimating more than 50 million people within the US suffering from some form of allergic disease. The natural history of allergic diseases suggests immunological crosstalk between mucosal organs contributes to the co-occurrences of allergic diseases (e.g. food allergy and asthma) within the same individual, although the cellular and molecular mechanisms that underly this process have not been defined and represent a critical knowledge gap. Using in vivo mouse models we have shown that intragastric administration of allergen (ovalbumin, OVA) to OVA-sensitized mice not only elicits local eosinophilic inflammation within the allergen-exposed intestine, but also increases the frequency and alters the activation phenotype of tissue eosinophils within the allergen non-challenged, remote lung. Presence of inflammatory eosinophils within the remote lung are associated with mucous metaplasia and airway priming; the latter evidenced by generation of an exacerbated allergic airway inflammatory response upon subsequent inhalation of sub-optimal doses of an unrelated antigen (house dust mite). In contrast, intragastric OVA failed to enhance mucous metaplasia or airway priming in the remote lungs of eosinophil deficient mice. Collectively these prior data suggest intragastric challenge affects allergic susceptibility of the airways through dysregulation of lung tissue eosinophils. This proposal builds on these findings to investigate lung- and eosinophil-intrinsic mechanisms that underly intragastric allergen-driven dysregulation of remote lung eosinophils that lead to remote airway priming. We have found intragastric allergen challenge transiently alters the lung transcriptome, including induction of gene signatures implicated in eosinophil recruitment. Correlative analyses of serum proteins and blood eosinophil-expressed receptors further suggest systemic mediators and eosinophil-intrinsic factors contribute specifically to lung homing, including an eosinophil-derived subset of extracellular vesicles (EVs). Specific Aims test the central hypothesis: Intragastric allergen challenge activates 1) an IL-13:CCL11 axis in the remote lung via gut-derived type 2 innate lymphoid cells (ILC2s), and 2) IL-5/IL-33:ST2-dependent effects on circulating eosinophils that synergistically underly the dysregulation of tissue eosinophils within the remote lung. Our approach utilizes unique genetically modified mouse strains, including cytokine reporter mice and cell-targeted gene disruption, competitive adoptive transfer studies and innovative approaches to characterize eosinophil-derived extracellular vesicles. Translational approaches utilize human blood eosinophils. Completion of this proposal may offer important insights into immunological mechanisms that drive mucosal remote organ priming within the context of allergic inflammation, and as such is highly relevant to the development of better diagnostic and interventional approaches for patients with allergic diseases.

抽象的 包括食物过敏和过敏性哮喘在内的过敏性疾病代表了实质性的健康和经济 负担，美国疾病控制中心（CDC）估计了美国境内超过5000万人 患有某种形式的过敏性疾病。过敏性疾病的自然病史表明免疫学 粘膜器官之间的串扰有助于过敏性疾病的共发生（例如，食物过敏和 哮喘）在同一个人中，尽管该过程的基础和分子机制 尚未定义并代表关键的知识差距。使用体内鼠标模型我们已经显示 胃内给药（卵蛋白，卵子）对卵子敏化的小鼠的胃内施用不仅引起局部局部 过敏原暴露肠内嗜酸性炎性炎症，但也会增加频率并改变 过敏原内组织嗜酸性粒细胞的激活表型，不受挑战，远程肺。存在 远端肺中的炎症性嗜酸性粒细胞与粘液化生和气道启动有关。 后者通过随后的加重过敏性气道炎症反应所证明 吸入不相关的抗原（房屋尘螨）的亚最佳剂量。相反，胃内OVA失败 为了增强嗜酸性粒细胞缺乏小鼠的偏远肺中的粘液化生或气道底漆。集体 这些先前的数据表明，胃内挑战会影响气道的过敏反应。 肺组织嗜酸性粒细胞的失调。该提案以这些发现为基础，以调查肺和 嗜酸性粒细胞 - 内部机制，这些机制是偏肺肺内驱动失调的基础肺内肺部的基础机制 导致远程气道底漆的嗜酸性粒细胞。我们发现胃内过敏原挑战瞬时改变 肺转录组，包括与嗜酸性粒细胞募集有关的基因特征的诱导。相关 血清蛋白和血液表达受体的分析进一步表明全身介质和 嗜酸性粒细胞 - 内神经因子特异性促进了肺归因，包括嗜酸性粒细胞衍生的子集 细胞外囊泡（EV）。特定目的测试中心假设：胃内过敏原挑战 激活1）通过肠道衍生的2型先天淋巴样细胞在遥控肺中的IL-13：CCL11轴 （ILC2S）和2）IL-5/IL-33：ST2依赖性对循环嗜酸性粒细胞的影响 偏远肺内组织嗜酸性粒细胞的失调。我们的方法从遗传上利用独特 修饰的小鼠菌株，包括细胞因子报告基因和细胞靶向基因破坏，竞争性 收养转移研究和创新方法，以表征嗜酸性粒细胞衍生的细胞外囊泡。 翻译方法利用人类血液嗜酸性粒细胞。该提案的完成可能会提供重要的 对在过敏性的背景下驱动粘膜远程器官启动的免疫机制的见解 炎症，因此与更好的诊断和介入的发展高度相关 过敏性疾病患者的方法。