Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

Wang, Ran; Moniruzzaman, Md.; Shuffle, Eric; Lourie, Rohan; Hasnain, Sumaira Z

Several endogenous factors can activate the UPR and hence alter the protein load of epithelial/ secretory cells. However, whether the immune system can have a direct effect on epithelial cells has received little attention. Some studies have demonstrated that inflammatory cytokines can induce oxidative stress within epithelial cells. [50] [51] [52] However, studies have mainly focused on epithelial cell-derived cytokines and/or chemokines rather than cytokines that affect epithelial cells. We demonstrated that specific inflammatory cytokines initiate ER stress by inducing oxidative stress, while other counteracting cytokines suppress stress and facilitate ER protein folding. 53 While this study focused on pancreatic b-cells, we have discovered that cytokine regulation of cellular stress is common to multiple epithelial cell types including intestinal and respiratory epithelial cells. In contrast, cytokines, such as IL-10 and IL-22, suppress ER stress and UPR activation, leading to increased mucus production, improved barrier function and attenuated intestinal mucosal inflammation in experimental colitis models. 52, 54 Immunity regulates protein production and secretion by non-immune cells by indirectly modulating the UPR ( Figure 2 ). As an instructive example of the ability of cytokines to modulate protein production, recent studies in our laboratory show that in chronic infection (nematode, Trichuris muris), the amount of ER stress and consequent Muc2 biosynthesis is dictated by an intact adaptive immune response (Figure 3 ). ER stress occurs in mice that mount a T H 1/17 response (low-dose infection), which show goblet cell pathology and fail to clear the infection. However, mice that mount a T H 2 response (high-dose infection) show high levels of goblet cell protein biosynthesis and secretion and go on to clear the infection. These data support our hypothesis of specific cytokines modulating protein production. Interestingly, ER stress is not observed in the immunodeficient mice that have chronic T. muris infection, strengthening our hypothesis of host intrinsic-induced cytokines being responsible for the activation of the UPR and induction of ER stress. We suggest that inflammatory cytokines have evolved to disrupt protein biosynthesis in cells prone to viral infection such as mucosal epithelial cells in order to reduce viral replication as a heretounrecognised element of the immune response.