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

Multiple animal models show that the UPR can be pathologically activated at several points when key components such as chaperones, transcription factors or key enzymes are absent or attenuated. Deletion of the major UPR transcription factor XBP1 in intestinal epithelial cells causes loss of mature Paneth cells, reduction in goblet cells, impaired bacterial handling and increased sensitivity to dextran sodium sulphate (DSS)induced colitis. 23 Ern2 À/À mice lacking ER-resident endonuclease, IRE1b, have increased Grp78 levels in intestinal epithelial cells and increased Muc2 misfolding, 2 which lead to increased susceptibility to DSS colitis. 24 Mice deficient in ATF6 have increased expression of ER stress genes and sensitivity to DSS colitis. 25 AGR2 is a protein disulphide isomerase involving in disulphide bond formation in proteins within the ER. Agr2 knockout mice have increased ER stress and suffer from a spontaneous granulomatous ileocolitis with goblet cell depletion. 26, 27 Aside from direct UPR component deficiency, abnormalities in proteins sequence or glycosylation sites also lead to the UPR activation and epithelial cell stress. Single missense mutation in Muc2 gene leads to misfolding of the major secreted intestinal mucin Muc2, resulting in a strong UPR response and subsequent development of spontaneous colitis characterised by activation of both innate and adaptive immunities with an IL-23/T H 17 phenotype. 28, 29 Immune-regulated alterations in mucin glycosylation following Trichuris muris infection contribute to clearance of parasitic infection. 30 Besides mucin secretion, a new underappreciated role of goblet cells (GCs) is antigen sampling through the goblet cellassociated antigen passages (GAPs) under homeostatic conditions. 31 Overriding GC microbial sensing to open colonic GAPs or inappropriate delivery of luminal pathogens through GAPs resulted in the influx of leucocytes and the production of inflammatory cytokines in the setting of normal, non-pathogenic, microbiota. 31, 32 This microbial sensing by colonic GCs has a critical role in regulating the exposure of the colonic immune system to luminal substances. Although detailed mechanisms are unknown, it presents an intriguing possibility that GC intrinsic UPR and autophagy pathways may be involved in this antigen trafficking process. Interestingly, as a host defence mechanism, GCs are able to shut off GAPs in response to intrinsic sensing of an invasive pathogen like Salmonella typhimurium via MyD88 signalling. 33 Another secretory cell in the small intestine is the highly specialised Paneth cell, which secretes antimicrobial molecules. 34, 35 The UPR plays an important role in Paneth cell production of antimicrobial peptides. Paneth cell-specific Xbp1 deletion is sufficient to induce ER stress and autophagy, which results in ileitis which is reversible under germ-free conditions. 11 The importance of Paneth cell secreting antimicrobial peptides is highlighted in the bacterial S. typhimurium infection model. The UPR activation and associated autophagy are required to ensure antimicrobial peptide secretion from Paneth cells during infection. 36 Besides the intrinsic UPR activation, extrinsic signals from innate lymphoid cells are also required. 36 The UPR not only regulates Paneth cell homeostasis, but also preserves its antimicrobial peptide secretory function during infections by increasing the UPR The UPR in airway epithelial barrier homeostasis Similar to intesti