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: 10418019
• 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/10418019
• 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; Home; 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; Lead; Lung; Lymphoid Cell; Mediating; Mediator of activation protein; 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; health economics; in vivo; innovation; insight; 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.

摘要 包括食物过敏和过敏性哮喘在内的过敏性疾病代表了严重的健康和经济问题。 美国疾病控制中心（CDC）估计，美国有超过5000万人 患有某种过敏性疾病过敏性疾病的自然史表明免疫 粘膜器官之间的串扰导致过敏性疾病（例如食物过敏和 哮喘）在同一个人，虽然细胞和分子机制，这一过程的基础 尚未界定，这是一个重大的知识差距。使用体内小鼠模型， 将过敏原（卵清蛋白，OVA）灌胃给致敏小鼠， 嗜酸性粒细胞性炎症在过敏原暴露的肠道，但也增加了频率和改变 过敏原未激发的远端肺内组织嗜酸性粒细胞的活化表型。存在 远端肺内的炎性嗜酸性粒细胞与粘液化生和气道启动有关; 后者的证据是在随后的过敏性气道炎症反应中产生了加重的过敏性气道炎症反应， 吸入次优剂量的无关抗原（屋尘螨）。相比之下，胃内OVA失败， 以增强嗜酸性粒细胞缺陷小鼠远端肺中的粘膜化生或气道启动。集体 这些先前的数据表明胃内激发通过以下途径影响气道的过敏易感性： 肺组织嗜酸性粒细胞失调。这项建议建立在这些发现的基础上， 嗜酸性粒细胞-胃内过敏原驱动远端肺失调的内在机制 嗜酸性粒细胞导致远程气道启动。我们已经发现胃内过敏原激发会短暂改变 肺转录组，包括诱导与嗜酸性粒细胞募集有关的基因签名。相关 对血清蛋白和血嗜酸性粒细胞表达受体的分析进一步提示全身介质和 嗜酸性粒细胞内源性因子对肺归巢有特异性作用，包括嗜酸性粒细胞衍生的亚群， 细胞外囊泡（EV）。特异性目的检验中心假设：胃内变应原激发 1）通过肠源性2型先天淋巴样细胞激活远端肺中的IL-13：CCL 11轴 IL-5/IL-33：ST 2对循环嗜酸性粒细胞的依赖性作用， 远端肺内组织嗜酸性粒细胞的失调。我们的方法利用独特的基因 修饰的小鼠品系，包括细胞因子报告小鼠和细胞靶向基因破坏， 过继转移研究和表征嗜酸性粒细胞衍生的细胞外囊泡的创新方法。 转化方法利用人血嗜酸性粒细胞。完成这项提案可能会提供重要的 深入了解在过敏性疾病背景下驱动粘膜远端器官启动的免疫学机制 炎症，因此与开发更好的诊断和干预方法高度相关。 过敏性疾病患者的治疗方法。