Type III interferon Control of Mucosal Immunity

免疫系统在组织损伤后控制修复的能力是保护宿主的基础

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.