Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia

Abstract

Respiratory viral infections are associated with an increased risk of asthma, but how acute Th1 antiviral immune responses lead to chronic inflammatory Th2 disease remains undefined. We define a novel pathway that links transient viral infection to chronic lung disease with dendritic cell (DC) expression of the high-affinity IgE receptor (FcεRIα). In a mouse model of virus-induced chronic lung disease, in which Sendai virus triggered a switch to persistent mucous cell metaplasia and airway hyperreactivity after clearance of replicating virus, we found that FceRIa−/− mice no longer developed mucous cell metaplasia. Viral infection induced IgE-independent, type I IFN receptor–dependent expression of FcεRIα on mouse lung DCs. Cross-linking DC FcεRIα resulted in the production of the T cell chemoattractant CCL28. FceRIa−/− mice had decreased CCL28 and recruitment of IL-13–producing CD4+ T cells to the lung after viral infection. Transfer of wild-type DCs to FceRIa−/− mice restored these events, whereas blockade of CCL28 inhibited mucous cell metaplasia. Therefore, lung DC expression of FcεRIα is part of the antiviral response that recruits CD4+ T cells and drives mucous cell metaplasia, thus linking antiviral responses to allergic/asthmatic Th2 responses.

Origin and functional specializations of DC subsets in the lung

“…Although type 1 interferons are massively produced by pDC during in vivo and in vitro influenza infection, many other cells, including epithelial cells and alveolar macrophages can produce this cytokine in vivo when pDC were depleted using antibodies [2]. pDC were shown to migrate to MLN following lung infection [2,9,53] but their role in viral antigen presentation seems negligible in vivo, as depletion of pDC prior to influenza infection did not modify clearance of the virus or induction of antiviral CD8 1 T lymphocytes. Another possibility that requires further exploration is the precise contribution of pDC to antiviral antibody production [2].…”

Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

“…In contrast to this concept, some animal models of early life infection suggest that virus infection could lead to allergic sensitization (4,5). In clinical studies, Sigurs and colleagues reported that respiratory syncytial virus (RSV) bronchiolitis leading to hospitalization during infancy was a risk factor not only for asthma but also for allergic sensitization at 13 years of age (6).…”

Structure-Function Analysis of CCL28 in the Development of Post-viral Asthma

“…The acute disease is dependent upon Th2 cells; however, the chronic form depends upon iNKT cells producing IL-13 and driving alternatively activated macrophage development. The alternatively activated macrophages produce IL-13, which maintains the disease and may drive even higher levels of mucous cell metaplasia (6,7). The mechanism connecting the acute to chronic disease is not known.…”

“…At the same time, IgE is produced against SeV, and subsequent cross-linking of IgE on the conventional dendritic cells leads to release of the chemokine CCL28, which then recruits Th2 cells to the airway. These Th2 cells produce IL-13 and drive the development of airway hyper-reactivity and mucous cell metaplasia, two hallmarks of asthma pathology (6). The SeV-induced disease includes both an acute form (develops by day 21 post-inoculation (PI) SeV) and a chronic form (develops by day 49 PI SeV) (7).…”