Title: IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection.
Authors: Shrestha, Bishwas; You, Dahui; Saravia, Jordy; Siefker, David T; Jaligama, Sridhar; Lee, Greg I; Sallam, Asmaa A; Harding, Jeffrey N; Cormier, Stephania A
Published In J Leukoc Biol, (2017 07)
Abstract: Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+ myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+ mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+ mDCs mainly present antigens to CD4+ T cells, we hypothesized that increased expression of IL-4Rα on neonatal CD11b+ mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+ cells were inversely correlated with maturation status of CD11b+ mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+ mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.
PubMed ID: 28389622
MeSH Terms: Animals; Animals, Newborn; CD11b Antigen/genetics; CD11b Antigen/immunology; Dendritic Cells/immunology*; Dendritic Cells/pathology; Disease Models, Animal; Mice; Mice, Inbred BALB C; Mice, Knockout; Receptors, Cell Surface/genetics; Receptors, Cell Surface/immunology*; Respiratory Syncytial Virus Infections/genetics; Respiratory Syncytial Virus Infections/immunology*; Respiratory Syncytial Virus Infections/pathology; Respiratory Syncytial Viruses/genetics; Respiratory Syncytial Viruses/immunology*; Th2 Cells/immunology*; Th2 Cells/pathology