We have discovered that immunity regulates protein synthesis in mucosal epithelial cells via the modulation of endoplasmic reticulum (ER) stress. Whilst it is well accepted that ER stress initiates inflammation via the unfolded protein response (UPR), the influence of local inflammatory cytokines on ER stress had received less attention. We show that IL-22 boosts ER protein folding, alleviates cellular stress and enhances protein production in secretory cells. Respiratory viruses utilize the host cellular machinery, including the ER to produce envelope proteins and replicate. We hypothesised that locally elevated IL-22 during viral infection could increase viral synthesis. Therefore, in this study IL-22 was therapeutically manipulated at appropriate times to help limit viral replication and mucosal tissue damage.
To confirm the cellular stress modulatory role of IL-22 in respiratory epithelial cells, we utilised the differentiated primary human bronchial epithelial cells (HBECs). IL-22 suppressed both cytokine (IL-23, IL-24, IL-17A, IFN-g) and N-glycosylation inhibitor tunicamycin induced ER stress, and promoted appropriate mucin production in HBECs. Supporting our hypothesis that IL-22 can boost protein synthesis, an increase in viral load was observed in HBECs infected with human Respiratory Syncytial Virus and Human Rhinovirus infected HeLa cells when treated with IL-22. In murine pneumovirus (PVM) infection, rIL-22 administration through the early stage of infection significantly increased viral replication and lead to severe lung injury including epithelial cell apoptosis and ~80% mortality before day 6 post infection. Neutralisation of IL-22 at day 3 post infection reduced airway mucin hyperplasia and immune cell infiltrate however lung injury and viral load were not significantly different from control group. Our data suggests that promoting ER stress at appropriate times during viral infection via blocking endogenous ER stress suppressor IL-22 could limit viral replication and immunopathology.