Unravelling a Novel Mechanism by which Cytokines Induce ER Stress to Halt Viral Protein Synthesis in Mucosal Epithelial Cells and its Implications for Sterile Inflammatory Diseases

Whilst it is accepted that endoplasmic reticulum (ER) stress initiates inflammatory signalling via the unfolded protein response, the influence of local inflammatory factors on ER stress remains unclear. We recently demonstrated in mucosal epithelial cells and pancreatic β-cells that specific inflammatory cytokines such as IL-17A, IL-23, IL-24 and IL-33 are potent initiators of oxidative stress, which induces protein misfolding and ER stress. Conversely, IL-22, and to a lesser extent, IL-10, suppress ER stress and facilitate protein folding^{1, 2}. Using a murine pneumovirus infection model, we now report that cytokine-induced ER stress prevents viral protein synthesis by mucosal epithelial cells. Neutralisation of IL-24 or administration of IL-22 through the early stage of infection increased pneumovirus replication, epithelial apoptosis and lung injury. In mouse models of non-infectious mucosal inflammation cytokine-induced ER stress is initiated inappropriately and exacerbates disease. For example, this mechanism explains the characteristic goblet cell depletion seen in colitis which leads to loss of mucus, exposing the epithelium to microbes and further exacerbating inflammation. In murine colitis neutralizing stressor cytokines or replenishing suppressor cytokines restored goblet cell mucin production.  While manipulation of cytokine-induced ER stress provides a therapeutic opportunity for inflammatory disease, consequences for viral infection need to be considered.

1.           Hasnain SZ, et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med 2014;20:1417-26.

2.           Hasnain SZ, et al. IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells. Gastroenterology 2013;144:357-368 e9.