Regulation and Function of Interferon-Lambda (IFNλ) and Its Receptor in Asthma

Abstract

Asthma is a chronic respiratory disease affecting people of all ages, especially children, worldwide. Origins of asthma are suggested to be placed in early life with heterogeneous clinical presentation, severity and pathophysiology. Exacerbations of asthma disease can be triggered by many factors, including viral respiratory tract infections. Rhinovirus (RV) induced respiratory infections are the predominant cause of the common cold and also play a crucial role in asthma development and exacerbations. Rhinovirus mainly replicates in epithelial cells lining the upper and lower respiratory tract. Type III interferons, also known as interferon-lambda (IFNλ), are potent immune mediators of resolution of infectious diseases but they are known to be involved in autoimmune diseases as well. The protective role of type III IFNs in antiviral, antibacterial, antifungal and antiprotozoal functions is of major importance for our innate immune system. The IFNλ receptor (IFNλR) is expressed in selected types of cells like epithelial cells, thus orchestrating a specific immune response at the site of viruses and bacteria entry into the body. In asthma, IFNλ restricts the development of TH2 cells, which are induced in the airways of asthmatic patients. Several studies described type III IFNs as the predominant type of interferon increased after infection caused by respiratory viruses. It efficiently reduces viral replication, viral spread into the lungs and viral transmission from infected to naive individuals. Several reports showed that bronchial epithelial cells from asthmatic subjects have a deficient response of type III interferon after RV infection ex vivo. Toll like Receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) expressed on infectious agents, and induce the development of antiviral and antibacterial immunity. We recently discovered that activation of TLR7/8 resulted in enhanced IFNλ receptor mRNA expression in PBMCs of healthy and asthmatic children, opening new therapeutic frontiers for rhinovirus-induced asthma. This article reviews the recent advances of the literature on the regulated expression of type III Interferons and their receptor in association with rhinovirus infection in asthmatic subjects.

Keywords: TLR7/8; asthma; epithelial cells; exacerbation; interferon; rhinovirus.

Figure 1

(A) Graphical illustration of the induction of type III interferon gene expression upon rhinovirus infection. HRV enters the cell via ICAM-1 receptor, CDHR3 receptor or via clathrin-mediated LDLR endocytosis. Viral cytosolic and endosomal ssRNA and dsRNA can be detected by PRR and PRM such as RIG-1 or MDA-5 (cytosolic) or TLR3 and TLR7/8 (endosomal), respectively. PRR and PRM induce downstream signaling cascades leading to recruitment of IRFs and NF-κB that promote type III interferon gene expression in the nucleus. (B) Graphical illustration of the signaling pathway after TLR 7 and 8 activation by resiquimod (R848). TLR 7 and 8 are located in intracellular vesicles, where they bind ssRNA or substances that mimic their structure. After activation, the signal is transduced via Myeloid differentiation primary response 88 (MyD88). Important mediators are TNF receptor-associated factor (TRAF) 3 and 6 as well as different interleukin-1 receptor associated kinase family members (IRAKs). Interferon regulatory factors (IRF) 3 and 7 and nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB) are the key regulatory factors that influence the gene expression in the nucleus. As a result the production of pro-inflammatory cytokines and type I interferons is enhanced.

Figure 2

Graphical illustration of the IFNλ family members production and release during virus infection (left) vs inflammation (right). Upon viral stimulation (1), the epithelial cells (2) and dendritic cells (3) are the main producers of type III interferons. The epithelial cell barrier therefore is the first defense line against viral infections. After the release of type III interferons, they bind to their specific receptor the IFNλR (4). This receptor is expressed on different cell types like macrophages, dendritic cells, neutrophils, B-cells and epithelial cells. During inflammatory processes, IFNλ activates dendritic cells to produce IL-12. This activates the Th1 immune response and thereby suppresses Th2 mediated inflammation like recruitment of eosinophils to the site of inflammation. Under these conditions, the Treg function is maintained and supports the lung homeostasis by resolving the airway inflammation.