Type III interferon Control of Mucosal Immunity

免疫系统控制组织损伤后修复的能力是保护宿主的基础 预防感染。胃肠道是探索其发病机制的理想组织。 组织损伤和修复之间的微妙平衡。炎症性肠病(IBD)是一组 异质性疾病，与导致遗传和环境因素有关，其特征是 通过组织修复保持炎症阶段的平衡。虽然IBD的病因尚不清楚，但IBD的一个特征是 这些炎症性疾病是一种慢性的、调节失调的免疫反应。尽管在以下方面取得了重大进展 阐明了控制组织损伤的机制，控制组织损伤的机制基础 免疫系统影响IBD发作后的恢复阶段，但尚未得到彻底的研究。干扰素 (IFN)是免疫反应中的关键角色，在IBD中增加。IFN属于三个族：类型 I型、II型和III型(也称为干扰素-λ)IFN。I型干扰素和干扰素-λ具有强大的抗病毒作用，均可诱导 一组相似的干扰素刺激基因(ISG)，被认为只起到多余的作用。我们最近 挑战这一范式，并表明干扰素λ，而不是I型IFN，通过以下方式限制小鼠结肠炎的炎症 抑制中性粒细胞的组织损伤功能。与干扰素-λ在调谐中的关键作用保持一致 在肠道炎症和维持健康的肠道环境方面，我们最近发现了两种 婴儿期出现干扰素-λS罕见破坏性突变导致缺陷的无关炎症性疾病患者 干扰素-λ受体信号转导。这种潜在的新的单基因紊乱与首次发现的抗-DNA缺陷直接相关。 病毒调控与IBD发病机制。尽管干扰素-λ具有抗病毒的特性，并限制炎症和组织 损伤，这组干扰素在肠道组织重建过程中的参与更具争议性。在保持 随着干扰素-λ在粘膜表面的有害作用，我们最近证明了干扰素λ延迟 持续病毒感染小鼠模型中肺上皮细胞的增殖和促进凋亡 新冠肺炎危重患者。通过观察干扰素λ在多种肠炎小鼠模型中的活性 损伤，我们现在揭示了由干扰素λ在肠上皮细胞中启动的一种新的分子级联，最终导致 以一种叫做下垂的细胞死亡的形式。我们的数据表明，干扰素λ延迟肠道恢复。我们假设 在炎症性肠病中，干扰素λ在肠道中起相反的作用。尽管干扰素λ抑制了组织损伤， 它可以延迟组织的重建，因为它对中性粒细胞或IECs的作用是分隔的。用人 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 干扰素λ的致病和保护作用，并寻找新的治疗靶点。为了达到我们的目标，我们将 地址：i)是什么驱动干扰素λ的产生，哪些细胞产生或应答干扰素λ；ii)什么是 IECs中控制热下垂诱导的信号级联成分；III)干扰素λ的产生 在儿童早期受到调节，以及它如何影响患者的IBD发展。

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.