Type III interferon Control of Mucosal Immunity

III 型干扰素控制粘膜免疫

• 批准号: 10587625
• 负责人: Scott B Snapper
• 金额: $ 77.74万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587625
• 关键词: Acute; Affect; Amphiregulin; Antiviral Response; Apoptosis; Bacteria; Biochemical; Biological Models; Biopsy; COVID-19 patient; Cell Death; Cell Line; Cells; Chronic; Colitis; Critical Illness; Data; Defect; Development; Disease; Enteral; Environment; Environmental Risk Factor; Epithelial Cells; Epithelium; Equilibrium; Etiology; Exposure to; Family; Flare; Gastrointestinal tract structure; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon Type I; Interferon Type II; Interferons; Intestines; Knowledge; Lamina Propria; Link; Lung; Mendelian disorder; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Mutation; Names; Organoids; Paneth Cells; Pathogenesis; Pathogenicity; Patients; Phase; Play; Production; Proliferating; Property; Proteins; Receptor Signaling; Regulation; Role; Signal Transduction; Small Intestines; Stimulus; Surface; Therapeutic; Therapeutic Intervention; Time; Tissues; Variant; Viral; Viral Physiology; Virus; Virus Diseases; cell type; early childhood; gastrointestinal epithelium; healing; human model; human tissue; infancy; inflammatory modulation; insight; intestinal epithelium; irradiation; member; microbial; microbial community; microbiota; mouse model; murine colitis; mutant; neutrophil; new therapeutic target; novel; novel therapeutic intervention; prevent; programs; receptor expression; repaired; response; spatiotemporal; systemic inflammatory response; therapeutically effective; tissue repair; virome

The capacity of the immune system to govern repair after tissue damage is fundamental to protect the host against infections. The gastrointestinal tract represents an ideal tissue to explore the mechanisms underlying the exquisite balance between tissue damage and repair. Inflammatory bowel diseases (IBDs) are a group of heterogenous disorders, associated with contributing genetic and environmental factors, that are characterized by inflammatory phases kept in balance by tissue repair. Although the etiology of IBDs is not clear, a hallmark of these inflammatory diseases is a chronic and dysregulated immune response. Despite significant progress in elucidating the mechanisms that govern tissue damage, the mechanistic underpinnings controlling how the immune system affects the restitution phase following IBD flares have not been thoroughly explored. Interferons (IFNs) are key players during an immune response and are increased in IBD. IFNs belong to three families: type I, type II, and type III (also known as IFN-λ) IFNs. Type I IFNs and IFN-λ play potent anti-viral roles, both inducing a similar set of IFN stimulated genes (ISGs) that were believed to play only redundant roles. We recently challenged this paradigm and showed that IFNλ, but not type I IFNs, limits inflammation during murine colitis by dampening the tissue damaging functions of neutrophils. In keeping with a key role of IFN-λ in tuning inflammation in the gut and in maintaining a healthy intestinal environment, we have recently identified two unrelated IBD patients presenting in infancy that have rare-damaging mutations in IFN-λs that lead to defective IFN-λ receptor signaling. This potential novel monogenic disorder links directly for the first-time defects in anti- viral regulation with IBD pathogenesis. Although IFN-λ has anti-viral properties and limits inflammation and tissue damage, the involvement of this group of IFNs during tissue restitution of the gut is more controversial. In keeping with a detrimental role of IFN-λ at mucosal surfaces, we have recently demonstrated that IFNλ delays proliferation and favors apoptosis of lung epithelial cells in mouse models of persistent viral infections and in critically ill COVID-19 patients. By investigating the activity of IFNλ in multiple mouse models of intestinal damage, we now revealed a new molecular cascade initiated by IFNλ in intestinal epithelial cells that culminates in a form of cell death called pyroptosis. Our data demonstrate that IFNλ delays gut restitution. We hypothesize that along the intestinal tract, IFNλ can play opposing roles during IBD. Although IFNλ dampens tissue damage, it can delay tissue restitution because of its compartmentalized action on either neutrophils or IECs. Employing murine and human model systems and human tissue, our goal is to decipher the mechanistic basis for both the pathogenic and protective roles of IFNλ and to identify new therapeutic targets. To reach our goals we will address: i) What drives the production of IFNλ, and which cells produce, or respond to, IFNλ; ii) What are the components of the signaling cascade that controls pyroptosis induction in IECs; iii) How the production of IFNλ is regulated during early childhood and how it impacts IBD development in patients.

免疫系统控制组织损伤后修复的能力对于保护宿主至关重要 防止感染。胃肠道是探索其潜在机制的理想组织 组织损伤与修复之间的微妙平衡。炎症性肠病（IBD）是一组 异质性疾病，与遗传和环境因素有关，其特征是 通过组织修复保持平衡的炎症阶段。尽管 IBD 的病因尚不清楚，但 IBD 的一个特点是 这些炎症性疾病是一种慢性且失调的免疫反应。尽管取得了重大进展 阐明控制组织损伤的机制，控制组织损伤的机制基础 免疫系统对 IBD 发作后恢复阶段的影响尚未得到彻底探索。干扰素 (IFN) 在免疫反应过程中发挥着关键作用，并且在炎症性肠病 (IBD) 中会增加。干扰素属于三个家族： 类型 I、II 型和 III 型（也称为 IFN-λ）干扰素。 I 型 IFN 和 IFN-λ 发挥有效的抗病毒作用，均诱导 一组类似的干扰素刺激基因（ISG）被认为只发挥多余的作用。我们最近 挑战了这一范式，并表明 IFNλ（而非 I 型 IFN）通过以下方式限制小鼠结肠炎期间的炎症： 抑制中性粒细胞的组织损伤功能。与 IFN-λ 在调节中的关键作用保持一致 肠道炎症和维持健康的肠道环境，我们最近发现了两种 不相关的 IBD 患者在婴儿期就诊，其 IFN-λ 具有罕见的破坏性突变，导致缺陷 IFN-λ 受体信号传导。这种潜在的新型单基因疾病与抗肿瘤药物的首次缺陷直接相关。 病毒调控与 IBD 发病机制。尽管 IFN-λ 具有抗病毒特性并限制炎症和组织 损伤，这组干扰素在肠道组织恢复过程中的参与更具争议性。为了保持 由于 IFN-λ 在粘膜表面具有有害作用，我们最近证明 IFN-λ 会延迟 在持续病毒感染的小鼠模型和小鼠模型中，促进肺上皮细胞增殖并促进其凋亡 重症 COVID-19 患者。通过研究多种小鼠肠道模型中 IFNλ 的活性 损伤，我们现在揭示了肠上皮细胞中由 IFNλ 引发的新分子级联反应，该级联反应最终达到顶峰 以一种称为焦亡的细胞死亡形式。我们的数据表明 IFNλ 会延迟肠道恢复。我们假设 沿着肠道，IFNλ 在 IBD 期间可以发挥相反的作用。尽管 IFNλ 可以抑制组织损伤， 它可以延迟组织恢复，因为它对中性粒细胞或 IEC 具有分隔作用。雇用 小鼠和人类模型系统和人体组织，我们的目标是破译两者的机制基础 IFNλ 的致病和保护作用并确定新的治疗靶点。为了实现我们的目标，我们将 地址：i) 是什么驱动 IFNλ 的产生，以及哪些细胞产生或响应 IFNλ； ii) 什么是 控制 IEC 中细胞焦亡诱导的信号级联的组成部分； iii) IFNλ如何产生 在儿童早期受到监管以及它如何影响患者 IBD 的发展。