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

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 过敏性疾病，包括食物过敏和过敏性哮喘，对健康和经济造成重大影响。 美国疾病控制中心 (CDC) 估计美国境内有超过 5000 万人 患有某种形式的过敏性疾病。过敏性疾病的自然史表明免疫学 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）在同一个体内，尽管这一过程背后的细胞和分子机制 尚未定义并且代表了一个关键的知识差距。使用我们已经展示的体内小鼠模型 向 OVA 致敏小鼠胃内施用过敏原（卵清蛋白，OVA）不仅会引起局部过敏 暴露于过敏原的肠道内的嗜酸性粒细胞炎症，也会增加频率并改变 未受到过敏原攻击的远端肺内组织嗜酸性粒细胞的激活表型。的存在 远端肺内的炎性嗜酸性粒细胞与粘液化生和气道预充有关； 后者的证据是随后的过敏性气道炎症反应加剧 吸入次优剂量的不相关抗原（屋尘螨）。相比之下，胃内OVA失败了 增强嗜酸性粒细胞缺乏小鼠远端肺部的粘液化生或气道启动。集体 这些先前的数据表明胃内挑战通过以下方式影响气道的过敏易感性 肺组织嗜酸性粒细胞失调。该提案建立在这些发现的基础上，调查肺和 胃内过敏原驱动的远端肺失调的嗜酸性粒细胞内在机制 导致远程气道预充的嗜酸性粒细胞。我们发现胃内过敏原挑战会短暂改变 肺转录组，包括诱导与嗜酸性粒细胞募集有关的基因特征。相关性 血清蛋白和血液嗜酸性粒细胞表达受体的分析进一步表明全身介质和 嗜酸性粒细胞内在因素特别有助于肺归巢，包括嗜酸性粒细胞衍生的子集 细胞外囊泡（EV）。具体目标测试中心假设：胃内过敏原挑战 1) 通过肠源性 2 型先天淋巴细胞激活远端肺部的 IL-13:CCL11 轴 （ILC2）和 2）IL-5/IL-33：ST2 对循环嗜酸性粒细胞的依赖性作用，其协同作用 远端肺内组织嗜酸性粒细胞失调。我们的方法利用独特的基因 改良小鼠品系，包括细胞因子报告小鼠和细胞靶向基因破坏、竞争性 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。 转化方法利用人类血液嗜酸性粒细胞。完成该提案可能会提供重要的 深入了解过敏背景下驱动粘膜远端器官启动的免疫机制 炎症，因此与更好的诊断和介入技术的发展高度相关 过敏性疾病患者的治疗方法。