Type III interferon Control of Mucosal Immunity

免疫系统在组织损伤后管理修复的能力是保护宿主的基础 对抗感染胃肠道是探索潜在机制的理想组织 组织损伤和修复之间的微妙平衡炎症性肠病（IBD）是一组 与遗传和环境因素有关的异质性疾病，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的一个标志是， 这些炎性疾病是一种慢性和失调的免疫反应。尽管取得了重大进展， 阐明了控制组织损伤的机制， 免疫系统影响IBD发作后的恢复期尚未得到彻底研究。干扰素 干扰素（IFN）是免疫应答过程中的关键参与者，并在IBD中增加。IFN属于三个家族： I型、II型和III型（也称为IFN-λ）IFN。I型IFN和IFN-λ发挥有效的抗病毒作用，两者都诱导 一组类似的IFN刺激基因（ISG），被认为只起冗余作用。我们最近 挑战了这种模式，并表明IFNλ，而不是I型IFN，通过以下方式限制了小鼠结肠炎期间的炎症： 抑制中性粒细胞的组织破坏功能。与IFN-λ在调节中的关键作用一致， 在肠道炎症和维持健康的肠道环境，我们最近确定了两个 在婴儿期出现的不相关IBD患者具有IFN-λ的罕见破坏性突变， IFN-λ受体信号传导。这种潜在的新型单基因疾病直接与抗- 病毒调节与IBD发病机制。尽管IFN-λ具有抗病毒特性， 损伤，这组干扰素在肠道组织恢复过程中的参与更有争议。一致 由于IFN-λ在粘膜表面的有害作用，我们最近证明IFN-λ延迟了 在持续性病毒感染的小鼠模型中， 重症新冠肺炎患者。通过研究IFNλ在多种肠上皮细胞模型中的活性， 损伤，我们现在揭示了一个新的分子级联启动IFNλ在肠上皮细胞， 一种叫做细胞凋亡的细胞死亡形式我们的数据表明IFNλ延迟肠道恢复。我们假设 在IBD期间，IFNλ在沿着肠道可以发挥相反的作用。虽然IFNλ抑制组织损伤， 由于其对中性粒细胞或IEC的区室化作用，其可延迟组织恢复。采用 鼠和人类模型系统和人体组织，我们的目标是破译这两个机制的基础， 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，哪些细胞产生或响应IFNλ; ii） 控制IEC中细胞凋亡诱导的信号级联的组成部分; iii）IFNλ的产生如何影响IEC中细胞凋亡的诱导。 在儿童早期受到调节，以及它如何影响IBD患者的发展。

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.