TY - JOUR
AU - Cao, Stewart, S.
AB - Abstract In eukaryotic cells, protein folding and modification in the endoplasmic reticulum (ER) is highly sensitive to disturbances of homeostasis. The accumulation of unfolded and misfolded proteins in the ER lumen, termed ER stress, activates intracellular signaling pathways to resolve the protein-folding defect. This unfolded protein response (UPR) increases the capacity of ER protein folding, reduces global protein synthesis, and activates ER-associated protein degradation. If ER stress is too severe or chronic, or the UPR is compromised and not able to restore ER protein-folding homeostasis, numerous apoptotic signaling pathways are activated. Preclinical and clinical studies in the past decade indicate that ER stress and the UPR have a significant impact on the pathogenesis of inflammatory bowel disease. Paneth and goblet cells, 2 epithelial cell populations in the gut, rely on a robust ER function for protein folding and secretion. Several immune cells are orchestrated by ER stress and the UPR for differentiation, activation, migration, and survival. In addition, a variety of exogenous and endogenous molecules in the intestinal lumen affect ER function, making ER stress and the UPR relevant cellular signals in intestinal homeostasis. Recent studies demonstrated that unresolved ER stress and/or dysregulated UPR may cause inflammatory bowel disease by inducing epithelial cell death, impairing mucosal barrier function, and activating proinflammatory response in the gut. With our increased understanding of ER stress in inflammatory bowel disease pathogenesis, it is now possible to develop novel therapies to improve ER protein-folding homeostasis and target-specific UPR pathways in cells residing in the intestinal mucosa. protein folding and secretion, apoptosis, intestinal epithelial cells, mucosal immunity, new therapies On the induction of endoplasmic reticulum (ER) stress in mammalian cells, the unfolded protein response (UPR) signaling is initiated by 3 protein sensors on the ER membrane: inositol-requiring kinase 1α (IRE1α), pancreatic ER eIF2α kinase (PERK), and activating transcription factor 6α (ATF6α). Under nonstressed conditions, binding of the ER chaperone BiP/GRP78 to the luminal domains of the ER stress sensors keeps them in an inactive state. According to the competition-binding model of UPR activation, unfolded/misfolded proteins in the ER lumen compete with IRE1, PERK, and ATF6 for binding to BiP. Accumulation of unfolded/misfolded proteins during ER stress activates the 3 sensors by dissociating BiP from their luminal domains (Fig. 1).1,2 Figure 1. Open in new tabDownload slide Mammalian UPR. The UPR in mammalian cells is mediated by 3 signaling pathways: the IRE1α-XBP1 pathway, the PERK-eIF2α-ATF4-CHOP pathway, and the ATF6α pathway. These UPR effectors play both overlapped and compensatory functions in many different cell types. Mitochondria are essential mediators in the induction of oxidative stress and apoptosis on ER stress. Figure 1. Open in new tabDownload slide Mammalian UPR. The UPR in mammalian cells is mediated by 3 signaling pathways: the IRE1α-XBP1 pathway, the PERK-eIF2α-ATF4-CHOP pathway, and the ATF6α pathway. These UPR effectors play both overlapped and compensatory functions in many different cell types. Mitochondria are essential mediators in the induction of oxidative stress and apoptosis on ER stress. IRE1, the most conserved ER stress transducer, is a type I transmembrane protein possessing both an endoribonuclease domain and a serine/threonine kinase domain in its cytosolic portion. Two IRE1 genes, IRE1α and IRE1β, have been identified in mice and human. IRE1α is expressed ubiquitously, whereas the expression of IRE1β is primarily restricted to the epithelial cells in the gut and respiratory tract. On the dissociation of BiP, the luminal domain of IRE1α undergoes homo-oligomerization and trans-autophosphorylation, which activates the endoribonuclease and kinase activities. Activated IRE1α removes a 26-base intron from a messenger RNA (mRNA), which results in a translational frame shift. This spliced mRNA is then translated to produce a cAMP response element–binding protein (CREB)/activating transcription factor (ATF) basic leucine zipper (bZIP)-containing transcription factor called X-box–binding protein 1 (XBP1). XBP1 orchestrates UPR signaling by inducing a number of genes that involves ER protein folding, secretion, phospholipid synthesis, ER expansion, and ER-associated protein degradation (ERAD). In addition to the cleavage of Xbp1 mRNA, the endoribonuclease domain of IRE1α targets a subset of ER-localized mRNAs on cellular stress, which was named regulated IRE1-dependent decay of mRNA (RIDD). RIDD suppresses ER-associated mRNA translation, thereby alleviating the burden of protein folding and maturation in the ER. Recently, RIDD was found to promote cell survival during early phase of ER stress by degrading mRNA encoding death receptor 5 (DR5), a member of tumor necrosis factor receptor superfamily that transduces apoptotic signal in the cell.3 As the most conserved ER stress transducer, IRE1α is required for murine embryonic development and the differentiation, survival and function of several secretory cells including pancreatic β cells, pancreatic acinar cells, plasma cells, and hepatocytes. Surprisingly, some cells endure prolonged ER stress better when IRE1α is genetically or pharmacologically inhibited. Several cellular pathways have been shown to contribute to the vicious side of IRE1α. As a protein kinase, IRE1α integrates the ER protein-folding disturbance with inflammatory and apoptotic signaling through the direct interaction with tumor necrosis factor alpha receptor-associated factor 2 (TRAF2) in the cytoplasm and subsequent activation of the NF-κB and c-Jun N-terminal kinase (JNK) pathways.1,2,4 Additionally, IRE1α induces mitochondrial-dependent cell death by binding to proapoptotic Bcl-2 family proteins Bax and Bak on the mitochondrial outer membrane. Although RIDD helps alleviate ER stress by attenuating ER-associated mRNA translation, prolonged/high ER stress can redirect RIDD to apoptotic activation through degradation of mRNAs encoding prosurvival proteins.1,5 Other reports showed that IRE1 can destroy some antiapoptotic microRNAs leading to cell death and inflammation.6,7 A recent study suggested that an increased oligomerization state and hyperactive endoribonuclease of IRE1α impair cellular homeostasis during severe/prolonged ER stress.8 ER stress sensor PERK is a type I transmembrane protein with a serine/threonine kinase domain on the cytosolic side. On ER stress, PERK becomes activated through homo-oligomerization and trans-autophosphorylation in a similar manner as IRE1. Activated PERK phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α) on Ser51, which impedes translation initiation thereby suppressing global protein synthesis and alleviating the ER protein-folding load. In mammals, 3 cytosolic kinases have been identified to phosphorylate eIF2α at Ser51. They are dsRNA-activated protein kinase (PKR), general control nonrepressed 2 kinase (GCN2), and heme-regulated eIF2α kinase (HRI), which respond to a broad spectrum of cellular disturbances through eIF2α phosphorylation-dependent signaling (termed integrated stress response). The translation inhibition mediated by eIF2α phosphorylation is usually transient and can be reversed by protein phosphatase 1 regulatory subunit 15A and B (also called GADD34 and CReP, respectively), which regulate the dephosphorylation of eIF2α. Although phosphorylated eIF2α functions to shut down global protein synthesis, it selectively enhances translation of a subset of mRNAs including an mRNA encoding bZIP transcription factor ATF4. Previous studies showed that ATF4 induces ER chaperones, UPR-associated transcription factors, as well as components of autophagy, antioxidative responses, and intracellular trafficking machinery. One downstream target of ATF4 is a bZIP transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP), which functions as a master regulator of ER stress–induced cell death.9 A number of signaling pathways have been linked to CHOP-mediated apoptosis. CHOP can kill cells by inhibiting prosurvival protein Bcl-2, as well as inducing proapoptotic factors Bim, DR5, and telomere repeat binding factor 3 (TRB3). On prolonged ER stress, CHOP directly leads to accumulation of DR5 protein, which undergoes ligand-independent activation and causes apoptosis through caspase-8 pathway.3 Studies suggested that oxidative stress and altered Ca2+ homeostasis also contribute to CHOP-induced cell death. ER oxidase 1α (ERO1α) promotes disulfide bond formation in oxidative protein folding in the ER lumen. During ER stress, CHOP induces the transcription of ERO1α, which may directly generate reactive oxygen species and contribute to oxidative damage in the cell. Furthermore, ERO1α results in Ca2+ release from the ER by stimulating inositol-1,4,5-trisphosphate receptor (IP3R) on the ER membrane, which leads to the activation of Ca2+-/calmodulin-dependent protein kinase II in the cytoplasm and downstream proapoptotic signaling.1,2,5 A recent study showed that ATF4 interacts with CHOP to transactivate genes encoding protein synthesis machinery, which then causes energy depletion, oxidative stress, and apoptosis in ER-stressed cells.10 As opposed to IRE1 and PERK, ATF6 is a type II transmembrane protein with a CREB/ATF bZIP domain at its N-terminus facing the cytoplasm. Mice and human possess 2 ATF6 genes, ATF6α and ATF6β. The α isoform induces UPR gene transcription in a number of cells, whereas the β isoform has a poorly understood (probably less important) role in ER function and homeostasis. Although neither Atf6α−/− nor Atf6β−/− mice exhibit significant abnormality under normal conditions, double knockout of Atf6α and Atf6β causes early lethality of murine embryos, suggesting some essential and overlapped functions of the 2 isoforms in embryonic development. ATF6 belongs to the family of regulated intramembrane proteolysis–regulated bZIP transcription factors. On ER stress induction, ATF6 dissociates from BiP and translocates to the Golgi apparatus, where it is cleaved by site-1–protease (S1P) and S2P sequentially at the transmembrane site. The freed cytosolic fragment (p50) of ATF6α migrates into the nucleus, where it transactivates ER chaperone genes including Grp78, P58IPK, and Grp94, induces ERAD components including Edem and Hrd1, and mediates ER biogenesis. ATF6α has been shown to promote protein folding, maturation, and secretion in ER-stressed cells. Some cells and tissues fail to survive prolonged ER stress in the absence of ATF6α. So far, several regulated intramembrane proteolysis–regulated bZIP transcription factors including CREBH, OASIS, and Luman have been identified. ER stress and other cellular signals activate these transcription factors, which play diverse and important roles in different types of cells.2,4 ER Stress and UPR in Intestinal Epithelial Cells Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), is the second most common inflammatory disease in the United States.11 Despite dozens of years of studies including 163 genomic loci identified to associate with IBD (90 loci with CD and 73 loci with UC),12 the etiology of this debilitating disease remains elusive. There is currently no cure for the disease that commonly requires a lifetime of care for patients with this chronic condition. Development of therapies for IBD faces an extraordinary challenge because of our poor understanding of the disease. Additionally, current medications that target the patients' immune system bring significant risks and side effects.13 The mammalian digestive tract is continuously exposed to a large number of antigens including trillions of microbes and various food metabolites. Intestinal homeostasis is achieved by sophisticated regulation of the immune response in the gut and peripheral tissues. Immune cell populations, including both innate and adaptive immune cells, play the central role in orchestrating the homeostasis-inflammation balance in gastrointestinal tract. Increased evidence suggests that the epithelial cells lining the bowel wall actively participate in the maintenance of mucosal homeostasis instead of functioning as an inert barrier. Murine and human intestinal epithelia contain 4 secretory cell types: Paneth, goblet, enteroendocrine, and absorptive cells, all of which are differentiated from a common constantly renewing Lgr5+ intestinal stem cell (ISC) population.14,15 Recently, the second stem cell pool (referred to as +4 population) was identified to harbor relatively quiescent, irradiation-resistant “reserve” stem cells, which can give rise to all the 4 intestinal epithelial cell (IEC) lines both in vivo and in vitro.16 Paneth cells are pyramid-like columnar epithelial cells that reside in the bottom of crypts of the small intestine17 and play a crucial role in innate immunity and host defense against bacteria, fungi, and some viruses. Paneth cells directly sense intestinal bacteria and their products through cell-autonomous MyD88-dependent Toll-like receptor activation, triggering expression and secretion of multiple antimicrobial factors including cryptdins/α-defensins, lysozyme, and phospholipase A2.18 Previous studies indicate that Paneth cells are essential for limiting the penetration by commensal and pathogenic microorganisms across the intestinal barrier, adjusting the balance among various bacterial populations, and maintaining intestinal homeostasis. The dysfunction of Paneth cells including reduced secretion of antimicrobial peptides has been linked to Crohn's ileitis.19 Goblet cells are mucin-producing cells in both small and large intestines. They secrete a large amount of gel-forming and cell-surface mucins under normal physiological conditions. MUC2 mucin, the major component of the mucus layer in the gut, undergoes N-glycosylation in the ER and O-glycosylation in the Golgi apparatus before being secreted into the intestinal lumen.20 The intestinal mucus layer prevents the infiltration of bacteria, viruses, fungi, and their products into the mucosa and is critical for intestinal homeostasis. Impaired goblet cell function, e.g., genetic ablation of Muc2, resulted in spontaneous colitis and colitis-associated colon cancer in mice.21 Goblet cell abnormalities, including decreased cell number and diminished mucin granules, are hallmarks of UC.22 However, the physiological importance of goblet cell pathology in UC is not fully understood. Recently, ER stress and the UPR have been linked to the pathogenesis of IBD.23 Human genetic studies of IBD have identified primary genetic abnormalities in several genes including XBP1, AGR2, and ORMDL3 that associate with ER protein folding and homeostasis.24 Animal studies demonstrated that the induction of ER stress through IEC-specific deletion of the gene encoding XBP1 results in the absence of Paneth cells and spontaneous inflammation in small intestine, along with impaired host defense to bacterial infection. Xbp1 conditional knockout mice displayed reduced number and defective mucin secretion of goblet cells in the gut.25 In addition, loss of Xbp1 alleles caused massive activation of IRE1α in ileal epithelium, which stimulated JNK and NF-κB pathways and production of inflammatory mediators in the mucosa. Further study showed that Paneth cell-specific ablation (Defa6-Cre) of Xbp1 leads to similar phenotype of spontaneous enteritis as observed in mice with total IEC deletion (Villin-Cre) of Xbp1, suggesting an essential role of the Paneth cell-specific UPR in mucosal homeostasis in mice.26 In the ER, AGR2 assists protein folding as a protein disulfide isomerase. Deletion of Agr2 leads to ER stress in the intestinal epithelium, disruption of Paneth cell homeostasis, and CD-like granulomatous ileocolitis.27 In another study, AGR2 was found to play a crucial role in the maturation and secretion of MUC2 mucin in murine colonic goblet cells.28,ORMDL3 encodes an ER-localized transmembrane protein, which is induced by allergens or interleukin (IL)-4/IL-13 in airway epithelial cells. ORMDL3 specifically activated ATF6α, which signals the transcription of ER Ca2+ ATPase SERCA2b during airway remodeling in asthma.29,30 However, the role ORMDL3 in IBD remains to be elucidated. In addition to the genes that have been associated with IBD, studies of other UPR components in mice also highlight the important role of ER stress in IEC function and intestinal homeostasis. IRE1β, an IRE1 isoform specifically expressed in mammalian gastrointestinal tract and airway mucous cells,31 was shown to protect against dextran sodium sulfate (DSS)-induced colitis in mice.32 This is the first study that linked the UPR to IEC function and intestinal inflammation. Recently, IRE1β was found to optimize the folding and secretion of MUC2 mucin in goblet cells by degrading Muc2 mRNA. In mice deleted in Ire1β, misfolded MUC2 precursors accumulated in the ER lumen of colonic goblet cells, which exhibited distended ER and induction of ER stress.33 How IRE1β regulates goblet cell function and mucosal homeostasis during enterocolitis and infection in the gut remains to be elucidated. In contrast, ablation of Chop alleviates DSS-induced colitis in mice.34 However, it is not clear whether this phenotype is due to the loss of CHOP in epithelial or hematopoietic cells because a whole-body deletion of Chop was used in that study. Another report showed that a hypomorphic mutation in the gene encoding S1P in mice increases the susceptibility to DSS-induced colitis.35 However, given S1P targets several ER stress–induced bZIP transcription factors including ATF6α/β, Luman, OASIS, CREBH, and SREBPs, it is possible that more than 1 of these transcription factors affects IEC function and mucosal homeostasis.2 Recently, OASIS was reported to control the terminal differentiation of goblet cells; whereas Oasis−/− mice exhibited abnormal ER and mucous vesicles in colonic goblet cells.36 On the challenge of DSS, Oasis−/− mice showed more severe signs of colitis with increased ER stress and apoptosis markers in IECs.37 Using a murine model with deletion of Atf6α in nonhematopoietic cells, it was shown that ATF6α mitigated DSS-induced colitis by inducing ER chaperone genes in colonic epithelial cells during inflammation. The protective role of ER chaperone response in IECs was further supported by experiments using P58IPK−/− mice, which displayed hyperactive inflammation in the colon with induced markers of ER stress and apoptosis after DSS challenge.38 Interestingly, some UPR components may play protein folding-unrelated roles in the pathogenesis of IBD. GRP94, an ER stress–induced ER cochaperone, was overexpressed on the apical surface of IECs in the ileum of patients with Crohn's ileitis and facilitated the invasion of pathogenic adherent-invasive Escherichia coli as a host cell receptor.39 However, the molecular mechanism of GRP94 in this process is unclear. The UPR interacts with other cellular signaling pathways, e.g., autophagy, in intestinal epithelial function and homeostasis. Autophagy controls Paneth cell function and has been associated with IBD.40 In patients with quiescent CD and healthy individuals who carry the ATG16L1 T300A risk allele, there were increased ER stress markers BiP and eIF2α phosphorylation in their Paneth cells. Although no change was observed in IEC proliferation or apoptosis, ISC number, NF-κB and p38 MAPK signaling in patients with ER-stressed Paneth cells, adherent-invasive E. coli was increased in the intestinal biopsies suggesting an impaired mucosal host defense.41 A recent study showed that loss of XBP1 induces autophagy in IEC, which is associated with activation of the PERK-eIF2α-ATF4 branch of the UPR. When both Xbp1 and Atg16l1 were deleted in IECs, mice developed spontaneous transmural inflammation in the ileim, which phenocopies Crohn's ileitis in humans. This double deletion resulted in the hyperactivation of IRE1α, NF-κB, tumor necrosis factor signaling and apoptosis of ileal IECs. These data suggest that XBP1 and autophagy play essential and partially compensatory roles in supporting Paneth cell function, suppressing proinflammatory signaling, and maintaining mucosal homeostasis in mice.26 In mice with IEC-specific expression of nonphosphorylatable eIF2α (AAIEC), there was a dramatic reduction of UPR-associated transcription factors and ER chaperones as well as an ablated autophagic activation in ileal IECs. AA Paneth cells exhibited decreased secretory proteins and diminished secretory granules, a fragmented ER, and degenerated mitochondria under electron microscopy. Translation of lysozyme and cryptidin mRNAs was significantly reduced with compromised ER protein translocation machinery including Sec11c, SSR1, and Sec63.42 Although AAIEC mice did not develop spontaneous enterocolitis as seen in Xbp1ΔIEC mice, they were more susceptible to Salmonella infection of ileum. These data suggest that eIF2α phosphorylation-dependent UPR signaling controls Paneth cell function by promoting ER protein translocation, protein folding in the ER, and autophagy.43 In addition to the phenotypes in the small bowel, both the AAIEC mice and mice lacking eIF2α kinase PKR in nonhematopoietic cells are more susceptible to DSS-induced colitis in the colon.43,–45 In addition to studies on specific UPR components, increasing evidence suggests that protein misfolding in the ER of IECs may directly contribute to IBD. Patients with active IBD exhibit signs of ER stress in their ileal and/or colonic epithelia with active disease.25,46,–48 Interestingly, the unaffected mucosal tissue of patients with UC showed lower level of eIF2α phosphorylation, suggesting an impaired integrated stress response that can be activated by various cellular stress conditions including ER stress, viral infection, inflammation, oxidative stress, amino acid deficiency, and heme depletion.49,50 Mice expressing a mutant Muc2 gene displayed increased accumulation of MUC2 precursor in the ER of goblet cells, reduced mucin secretion, an impaired mucus layer, as well as activation of innate and adaptive immunity with an induced Th17 response in the colon, which is similar to that of human UC.47,51 Importantly, some patients with UC also exhibited accumulation of MUC2 precursors in the ER of colonic goblet cells, suggesting that protein-folding defect is physiologically relevant to goblet cell pathology in the pathogenesis of UC.36 Later, the same group showed that IL-10, an anti-inflammatory cytokine crucial for intestinal homeostasis, mitigates ER stress and promotes mucin secretion in goblet cells.52 Recently, they reported that glucocorticoids improve the folding and secretion of mutant MUC2 mucin and alleviate intestinal inflammation by inducing ER chaperones and ERAD components in goblet cells.53 ATP-binding cassette G2 (ABCG2), a xenobiotic transporter expressed in IECs, protects intestinal epithelium from exogenous and endogenous toxins and maintains epithelial integrity.54 A recent study showed that the protein level of ABCG2 negatively correlates with ER stress marker BiP in small and large bowels of patients with active IBD, ischemic colitis, and infectious colitis. Inflammatory stimuli and ER stress inducers shut down the intracellular transport and plasma membrane localization of ABCG2 in cell culture.55 This study suggested that inflammation impedes the transport of ABCG2 to IEC surface in a nonspecific manner, which may involve a compromised ER protein folding function. However, it remains unknown whether ER stress is necessary and sufficient to disrupt ABCG2 transport and activity in IECs during mucosal inflammation. ER stress may contribute to IBD through disruption of ionic homeostasis in IECs. Elevated potassium efflux and calcium influx were observed in cultured colonic epithelial cells on ER stress; whereas pharmacological inhibition of potassium efflux reduced ER stress–induced apoptosis in these cells.56 Future studies should determine the molecular mechanism and physiological significance of this process in IBD pathogenesis (Fig. 2). Figure 2. Open in new tabDownload slide ER stress and the UPR in IECs during IBD pathogenesis. Green: UPR effectors that support IEC function and prevent mucosal inflammation; Red: proteins that impair IEC function and homeostasis and induce/exacerbate intestinal inflammation; Blue: small molecular compounds that alleviate intestinal inflammation in murine models of IBD by suppressing ER stress and/or enhancing adaptive UPR in IECs. Figure 2. Open in new tabDownload slide ER stress and the UPR in IECs during IBD pathogenesis. Green: UPR effectors that support IEC function and prevent mucosal inflammation; Red: proteins that impair IEC function and homeostasis and induce/exacerbate intestinal inflammation; Blue: small molecular compounds that alleviate intestinal inflammation in murine models of IBD by suppressing ER stress and/or enhancing adaptive UPR in IECs. In addition to mature IECs, emerging evidence suggests that ER stress and UPR also impact the self-renewal and differentiation of ISCs in mice. In murine intestine, a physiologic UPR was observed during the transition from ISCs to transit-amplifying cells. Pharmacological and genetic induction of ER stress caused a loss of LGR5+ ISCs; whereas suppression of the PERK-eIF2α pathway using RNAi and chemical inhibitors led to expansion of LGR5+ ISCs in organoid culture of intestinal epithelium.57 In contrast, a recent study using mice with IEC-specific expression of nonphosphorylatable eIF2α (AAIEC) showed that eIF2α phosphorylation is dispensable for the self-renewal and differentiation of LGR5+ ISCs in vivo.43 An organoid culture experiment using AA ISCs could provide additional insight into the function of eIF2α phosphorylation in ISCs. The deletion of Xbp1 in intestinal epithelium resulted in an expansion of LGR5+/OLFM+ ISCs and increased proliferation of transit-amplifying cells, which required the activation of IRE1α and STAT3, respectively. As a consequence, Xbp1ΔIEC mice were prone to developing colitis-associated and spontaneous adenomatous polyposis coli-related tumors in the gut.58 Toll-like receptor 4 was found in murine ISCs and may contribute to ISC death in necrotizing enterocolitis.59 Recent study suggested that Toll-like receptor 4 specifically activates the PERK-CHOP branch (but not ATF6α or IRE1α) of the UPR, which then leads to the apoptosis of ISCs in a murine model of necrotizing enterocolitis.60 Our understanding of ISC has been evolving rapidly thanks to the recent progresses on +4 stem cell populations.16 Future studies should determine how specific UPR components regulate the self-renewal, interconversion, and differentiation of distinct ISC populations and how they affect mucosal homeostasis in IBD. ER Stress and UPR in Immune Cell Function Another exciting direction in the ER stress-IBD research is how ER stress/UPR regulates the differentiation, activation, migration, and survival of immune cells, such as macrophages, neutrophils, natural killer cells, dendritic cells (DCs), T cells, and B cells in the pathogenesis of IBD. Cells expressing misfolding-prone proteins are at increased risk of developing ER stress. The major histocompatibility complex class I allele HLA-B27 contributes to spondyloarthritis, which inflames multiple organs including the small intestine. HLA-B27 heavy chain undergoes misfolding in the ER and activates the UPR and ERAD in inflammatory cells.61 HLA-B27/human b2-microglobulin transgenic rats developed spontaneous colitis with induction of IL-23 and IL-17 in CD11+ antigen-presenting cells and CD4+ T cells, respectively.62 However, it is unclear which UPR component(s) mediates the activation of Th17 response in this model. In TnfΔARE mice, a genetic model of Crohn's ileitis, ER stress induced by ablation of 1 allele of ER chaperone gene Grp78 elevated the cytotoxicity of CD8αβ+ intraepithelial lymphocytes in the ileum.63 This is one of the first studies directly examining how ER stress impacts immune cell function in animal models of IBD. However, mice with whole-body deletion of one Grp78 allele was used in this study, which raises the question whether ER stress in the epithelial cells, fibroblasts, as well as other immune cells, has also contributed to the phenotype. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that suppress the immune response by inhibiting T-cell proliferation and activation. Adaptive transfer of MDSCs was shown to dampen intestinal inflammation in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice.64 A recent study suggested that the ER stress induced in tumor microenvironment caused apoptotic cell death of MDSCs, thereby promoting inflammation and tumor growth.65 It remains to be determined how ER stress regulates the survival and function of MDSCs in IBD pathogenesis. More than a decade ago, XBP1 was first shown to control the differentiation of plasma cell.66 Since then, the list of immune cells that are orchestrated by the IRE1α-XBP1 pathway has been growing to include macrophages, T cells, and DCs.67,–83 A recent study suggested that XBP1 and IRE1α played independent but closely related roles in CD8α+ DCs. All splenic DCs, especially the CD8α+ DCs, constitutively activated the IRE1α-XBP1 pathway. CD8α+ DCs with deletion of Xbp1 exhibited a distended ER and blunted expression of XBP1-targeted genes including Erdj5, Erp44, Tpp1, and Rpn1. In addition, Xbp1−/− CD8α+ DCs displayed an impaired antigen presentation by MHC-I molecules. The phenotype was probably due to the hyperactivated RIDD of mRNA encoding TAP binding protein in DCs, since this defect was not observed in Ire1α−/− CD8α+ DCs.84 CHOP is important for caspase-11–mediated IL-1β secretion in lung and cultured macrophages.85 Recently, CHOP was reported to induce IL-23 expression in DCs, which is critical for the Th17 response in the mucosa and IBD pathogenesis.86 GRP94 was induced in intestinal macrophages of healthy individuals and patients with UC and diverticulitis, but not in patients with CD.87 However, the function of GRP94 in intestinal macrophages and CD is unknown. pERp1 is an ER-localized protein involved in antibody secretion and integrin-mediated adhesion of B cells. pERp1 was recently reported to bind with GRP94 and is required for the interaction of GRP94 with immunoglobulin μ heavy chain in ER-stressed B cells. In absence of pERp1, pro-B-cell to pre-B-cell differentiation is blocked on tunicamycin-induced ER stress in vivo.88 ORMDL3 was shown to regulate T-cell activation by inhibiting Ca2+ influx at the outer mitochondrial membrane with an elusive mechanism.29,30 Future studies should perform conditional deletion/overexpression of specific UPR regulators and effectors in CD and UC models to investigate their impact on immune response in the gut. ER Stress and UPR in IBD Therapeutics The critical role of ER homeostasis in IEC function suggests that ER stress–alleviating compounds could be therapies for IBD. Recently, study demonstrated that the chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylburyrate (PBA), 2 FDA-approved compounds, reduces ER stress in cultured IECs treated with inflammatory stimuli. Feeding of either TUDCA or PBA mitigated intestinal inflammation in DSS-induced, Il-10−/− and TnfΔARE murine models of IBD by alleviating ER stress in the IECs.38 It is unclear how chemical chaperones act on other cell types including immune cells and fibroblasts in the gut on inflammatory insults. In ApoE−/− mice model of atherosclerosis, treatment of PBA induced the expression of IL-10, IL-35, and Foxp3 with elevated number of T regulatory cells (Tregs), which helped dampen the chronic inflammation in the arterial wall.89 Given the importance of CD4+Foxp3+ Tregs as well as IL-10 and IL-35 in mucosal homeostasis,90,91 future studies should determine how PBA affect the differentiation, activation, and migration of Tregs and other immune cells in IBD models. Salubrinal is a small molecular compound that maintains/prolongs eIF2α phosphorylation by inhibiting GADD34 activity.92 Recently, salubrinal was shown to mitigate the spontaneous UC-like phenotype in a new murine model with double deficiency of IL-10 and nicotinamide adenine dinucleotide phosphate-oxidase 1.93 However, it remains unknown how eIF2α phosphorylation functions in different cell populations in the colon and helps to restore mucosal homeostasis in this model. Glutamine is an important fuel for rapidly dividing cells including IECs. It was reported that glutamine improved TNBS-induced colitis in rats by reducing ER stress, oxidative stress, inflammatory response, and apoptosis in colonic epithelial cells. Similarly, glutamine was able to suppress chemically induced ER stress in cultured Caco-2 cells.94 Future studies should determine whether glutamine directly assists protein folding in the ER or alleviates ER stress through other mechanism(s) such as energy homeostasis and mitochondrial function in IECs (Fig. 2). Discussion The epithelial layer plays a crucial role in maintaining intestinal homeostasis as an interface between the exogenous molecules, microbiota, and the immune system. The failure of IECs to modulate inflammatory responses may dramatically impair mucosal homeostasis and directly cause IBD. Previous studies demonstrated that cells with a high load of protein folding and secretion are sensitive to altered ER homeostasis, which can also induce inflammatory gene expression.95,96 Environmental signals including microbial molecules, bile salts, and cholinergic stimuli as well as host innate and adaptive immune mediators stimulate the biosynthesis, maturation, and secretion of antimicrobial peptides and mucins through pathways including the NF-κB signaling.97,–99 The augmented production of antimicrobial peptides and mucins can overwhelm the protein secretory capacity of Paneth and goblet cells. Meanwhile, inflammatory and oxidative stimuli may disturb ER homeostasis and cause ER stress, although the precise mechanisms are not well understood.95 On exposure to high levels of exogenous antigens, inflammatory cytokines as well as toxins and reactive oxidative/nitrosative species in the intestinal lumen, IECs may require an intact UPR signaling, including ER chaperones, protein transport, and ERAD, to survive the heavy burden of protein folding, maturation, and secretion. In contrast, chronic ER stress and a defective UPR may impair the function and homeostasis of IECs, which may cause epithelial cell death, impair barrier function, and lead to intestinal inflammation. The induced ER stress markers in the intestinal epithelia of patients with CD and UC, the UPR genes associated with IBD, as well as evidence derived from animal studies all suggest that a perturbed ER homeostasis due to environmental stress or genetic lesions in IECs may contribute to the pathogenesis of IBD. During past decade, several UPR components have been studied in IEC function in animal models. However, there is limited information regarding how the UPR pathways function in IECs in different IBD models, such as chemical-induced models, cell transfer into immune-deficient mice, knockout models, transgenic/knockin models, and spontaneous models.11 Studies of ER stress/UPR using different models may shed light on the role of these signaling pathways in different aspects of IBD pathophysiology. In addition, lack of good cell culture models of primary IECs, especially Paneth cells, also impedes our understanding of ER stress/UPR in IEC function and homeostasis. Given the difficulty of culturing mature IECs in vitro, differentiation of primary ISCs into epithelial organoids that include Paneth and goblet cells may be a promising new direction. Acknowledgments The author thanks Dr. Randal Kaufman at Sanford-Burnham Medical Research Institute for discussions. References 1. Hetz C . The unfolded protein response: controlling cell fate decisions under ER stress and beyond . Nat Rev Mol Cell Biol . 2012 ; 13 : 89 – 102 . Google Scholar PubMed WorldCat 2. Cao SS , Kaufman RJ . Unfolded protein response . Curr Biol . 2012 ; 22 : R622 – R626 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Lu M , Lawrence DA , Marsters S , et al. . Cell death. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis . Science . 2014 ; 345 : 98 – 101 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Walter P , Ron D . The unfolded protein response: from stress pathway to homeostatic regulation . Science . 2011 ; 334 : 1081 – 1086 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Tabas I , Ron D . Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress . Nat Cell Biol . 2011 ; 13 : 184 – 190 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Lerner AG , Upton JP , Praveen PV , et al. . IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress . Cell Metab . 2012 ; 16 : 250 – 264 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Upton JP , Wang L , Han D , et al. . IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2 . Science . 2012 ; 338 : 818 – 822 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Ghosh R , Wang L , Wang ES , et al. . Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress . Cell . 2014 ; 158 : 534 – 548 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Rutkowski DT , Arnold SM , Miller CN , et al. . Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins . PLoS Biol. 2006 ; 4 : e374 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Han J , Back SH , Hur J , et al. . ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death . Nat Cell Biol . 2013 ; 15 : 481 – 490 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Corridoni D , Arseneau KO , Cominelli F . Inflammatory bowel disease . Immunol Lett . 2014 ; 161 : 231 – 235 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Deuring JJ , de Haar C , Kuipers EJ , et al. . The cell biology of the intestinal epithelium and its relation to inflammatory bowel disease . Int J Biochem Cell Biol . 2013 ; 45 : 798 – 806 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Dahan A , Amidon GL , Zimmermann EM . Drug targeting strategies for the treatment of inflammatory bowel disease: a mechanistic update . Expert Rev Clin Immunol . 2010 ; 6 : 543 – 550 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Barker N , van Es JH , Kuipers J , et al. . Identification of stem cells in small intestine and colon by marker gene Lgr5 . Nature . 2007 ; 449 : 1003 – 1007 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Sato T , Vries RG , Snippert HJ , et al. . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche . Nature . 2009 ; 459 : 262 – 265 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Leushacke M , Barker N . Ex vivo culture of the intestinal epithelium: strategies and applications . Gut . 2014 ; 63 : 1345 – 1354 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Porter EM , Bevins CL , Ghosh D , et al. . The multifaceted Paneth cell . Cell Mol Life Sci . 2002 ; 59 : 156 – 170 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Vaishnava S , Behrendt CL , Ismail AS , et al. . Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface . Proc Natl Acad Sci U S A . 2008 ; 105 : 20858 – 20863 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Garrett WS , Gordon JI , Glimcher LH . Homeostasis and inflammation in the intestine . Cell . 2010 ; 140 : 859 – 870 . Google Scholar Crossref Search ADS PubMed WorldCat 20. van Ooij C . Stuck to MUC2. Nat Rev Microbiol. 2010 ; 8 : 463 . Google Scholar Crossref Search ADS PubMed WorldCat 21. Velcich A , Yang W , Heyer J , et al. . Colorectal cancer in mice genetically deficient in the mucin Muc2 . Science . 2002 ; 295 : 1726 – 1729 . Google Scholar Crossref Search ADS PubMed WorldCat 22. McGuckin MA , Eri RD , Das I , et al. . Intestinal secretory cell ER stress and inflammation . Biochem Soc Trans . 2011 ; 39 : 1081 – 1085 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Kaser A , Blumberg RS . Endoplasmic reticulum stress in the intestinal epithelium and inflammatory bowel disease . Semin Immunol . 2009 ; 21 : 156 – 163 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Maloy KJ , Powrie F . Intestinal homeostasis and its breakdown in inflammatory bowel disease . Nature . 2011 ; 474 : 298 – 306 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Kaser A , Lee AH , Franke A , et al. . XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease . Cell . 2008 ; 134 : 743 – 756 . Google Scholar Crossref Search ADS PubMed WorldCat 26. Adolph TE , Tomczak MF , Niederreiter L , et al. . Paneth cells as a site of origin for intestinal inflammation . Nature . 2013 ; 503 : 272 – 276 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Zhao F , Edwards R , Dizon D , et al. . Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2−/− mice . Dev Biol . 2010 ; 338 : 270 – 279 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Park SW , Zhen G , Verhaeghe C , et al. . The protein disulfide isomerase AGR2 is essential for production of intestinal mucus . Proc Natl Acad Sci U S A . 2009 ; 106 : 6950 – 6955 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Miller M , Tam AB , Cho JY , et al. . ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6 . Proc Natl Acad Sci U S A . 2012 ; 109 : 16648 – 16653 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Carreras-Sureda A , Cantero-Recasens G , Rubio-Moscardo F , et al. . ORMDL3 modulates store-operated calcium entry and lymphocyte activation . Hum Mol Genet . 2013 ; 22 : 519 – 530 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Martino MB , Jones L , Brighton B , et al. . The ER stress transducer IRE1beta is required for airway epithelial mucin production . Mucosal Immunol . 2013 ; 6 : 639 – 654 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Bertolotti A , Wang X , Novoa I , et al. . Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice . J Clin Invest . 2001 ; 107 : 585 – 593 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Tsuru A , Fujimoto N , Takahashi S , et al. . Negative feedback by IRE1beta optimizes mucin production in goblet cells . Proc Natl Acad Sci U S A . 2013 ; 110 : 2864 – 2869 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Namba T , Tanaka K , Ito Y , et al. . Positive role of CCAAT/enhancer-binding protein homologous protein, a transcription factor involved in the endoplasmic reticulum stress response in the development of colitis . Am J Pathol . 2009 ; 174 : 1786 – 1798 . Google Scholar Crossref Search ADS PubMed WorldCat 35. Brandl K , Rutschmann S , Li X , et al. . Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response . Proc Natl Acad Sci U S A . 2009 ; 106 : 3300 – 3305 . Google Scholar Crossref Search ADS PubMed WorldCat 36. Asada R , Saito A , Kawasaki N , et al. . The endoplasmic reticulum stress transducer OASIS is involved in the terminal differentiation of goblet cells in the large intestine . J Biol Chem . 2012 ; 287 : 8144 – 8153 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Hino K , Saito A , Asada R , et al. . Increased susceptibility to dextran sulfate sodium-induced colitis in the endoplasmic reticulum stress transducer OASIS deficient mice . PLoS One. 2014 ; 9 : e88048 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Cao SS , Zimmermann EM , Chuang BM , et al. . The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice . Gastroenterology . 2013 ; 144 : 989 – 1000 .e6. Google Scholar Crossref Search ADS PubMed WorldCat 39. Rolhion N , Barnich N , Bringer MA , et al. . Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion . Gut . 2010 ; 59 : 1355 – 1362 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Van Limbergen J , Radford-Smith G , Satsangi J . Advances in IBD genetics . Nat Rev Gastroenterol Hepatol . 2014 ; 11 : 372 – 385 . Google Scholar Crossref Search ADS PubMed WorldCat 41. Deuring JJ , Fuhler GM , Konstantinov SR , et al. . Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease . Gut . 2014 ; 63 : 1081 – 1091 . Google Scholar Crossref Search ADS PubMed WorldCat 42. Aviram N , Schuldiner M . Embracing the void-how much do we really know about targeting and translocation to the endoplasmic reticulum? Curr Opin Cell Biol. 2014 ; 29C : 8 – 17 . Google Scholar Crossref Search ADS WorldCat 43. Cao SS , Wang M , Harrington JC , et al. . Phosphorylation of eIF2alpha is dispensable for differentiation but required at a posttranscriptional level for paneth cell function and intestinal homeostasis in mice . Inflamm Bowel Dis . 2014 ; 20 : 712 – 722 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Cao SS , Song B , Kaufman RJ . PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling . Inflamm Bowel Dis . 2012 ; 18 : 1735 – 1742 . Google Scholar Crossref Search ADS PubMed WorldCat 45. Cao SS , Kaufman RJ . PKR in DSS-induced colitis: a matter of genetic background and maternal microflora? Inflamm Bowel Dis. 2013 ; 19 : E49 – E50 . Google Scholar Crossref Search ADS PubMed WorldCat 46. Shkoda A , Ruiz PA , Daniel H , et al. . Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation . Gastroenterology . 2007 ; 132 : 190 – 207 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Heazlewood CK , Cook MC , Eri R , et al. . Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis . PLoS Med. 2008 ; 5 : e54 . Google Scholar Crossref Search ADS PubMed WorldCat 48. Hu S , Ciancio MJ , Lahav M , et al. . Translational inhibition of colonic epithelial heat shock proteins by IFN-gamma and TNF-alpha in intestinal inflammation . Gastroenterology . 2007 ; 133 : 1893 – 1904 . Google Scholar Crossref Search ADS PubMed WorldCat 49. Treton X , Pedruzzi E , Cazals-Hatem D , et al. . Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis . Gastroenterology . 2011 ; 141 : 1024 – 1035 . Google Scholar Crossref Search ADS PubMed WorldCat 50. Ron D , Walter P . Signal integration in the endoplasmic reticulum unfolded protein response . Nat Rev Mol Cell Biol . 2007 ; 8 : 519 – 529 . Google Scholar Crossref Search ADS PubMed WorldCat 51. Eri RD , Adams RJ , Tran TV , et al. . An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity . Mucosal Immunol . 2011 ; 4 : 354 – 364 . Google Scholar Crossref Search ADS PubMed WorldCat 52. Hasnain SZ , Tauro S , Das I , 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 . Google Scholar Crossref Search ADS PubMed WorldCat 53. Das I , Png CW , Oancea I , et al. . Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins . J Exp Med . 2013 ; 210 : 1201 – 1216 . Google Scholar Crossref Search ADS PubMed WorldCat 54. Dietrich CG , Geier A , Oude Elferink RP . ABC of oral bioavailability: transporters as gatekeepers in the gut . Gut . 2003 ; 52 : 1788 – 1795 . Google Scholar Crossref Search ADS PubMed WorldCat 55. Deuring JJ , de Haar C , Koelewijn CL , et al. . Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding . Biochem J . 2012 ; 441 : 87 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat 56. Shabala L , Walker EJ , Eklund A , et al. . Exposure of colonic epithelial cells to oxidative and endoplasmic reticulum stress causes rapid potassium efflux and calcium influx . Cell Biochem Funct . 2013 ; 31 : 603 – 611 . Google Scholar PubMed WorldCat 57. Heijmans J , van Lidth de Jeude JF , Koo BK , et al. . ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response . Cell Rep . 2013 ; 3 : 1128 – 1139 . Google Scholar Crossref Search ADS PubMed WorldCat 58. Niederreiter L , Fritz TM , Adolph TE , et al. . ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells . J Exp Med . 2013 ; 210 : 2041 – 2056 . Google Scholar Crossref Search ADS PubMed WorldCat 59. Neal MD , Sodhi CP , Jia H , et al. . Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the p53 up-regulated modulator of apoptosis . J Biol Chem . 2012 ; 287 : 37296 – 37308 . Google Scholar Crossref Search ADS PubMed WorldCat 60. Afrazi A , Branca MF , Sodhi CP , et al. . Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis . J Biol Chem . 2014 ; 289 : 9584 – 9599 . Google Scholar Crossref Search ADS PubMed WorldCat 61. Colbert RA , Tran TM , Layh-Schmitt G . HLA-B27 misfolding and ankylosing spondylitis . Mol Immunol . 2014 ; 57 : 44 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat 62. DeLay ML , Turner MJ , Klenk EI , et al. . HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats . Arthritis Rheum . 2009 ; 60 : 2633 – 2643 . Google Scholar Crossref Search ADS PubMed WorldCat 63. Chang JS , Ocvirk S , Berger E , et al. . Endoplasmic reticulum stress response promotes cytotoxic phenotype of CD8alphabeta+ intraepithelial lymphocytes in a mouse model for Crohn's disease-like ileitis . J Immunol . 2012 ; 189 : 1510 – 1520 . Google Scholar Crossref Search ADS PubMed WorldCat 64. Guan Q , Moreno S , Qing G , et al. . The role and potential therapeutic application of myeloid-derived suppressor cells in TNBS-induced colitis . J Leukoc Biol . 2013 ; 94 : 803 – 811 . Google Scholar Crossref Search ADS PubMed WorldCat 65. Condamine T , Kumar V , Ramachandran IR , et al. . ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis . J Clin Invest . 2014 ; 124 : 2626 – 2639 . Google Scholar Crossref Search ADS PubMed WorldCat 66. Reimold AM , Iwakoshi NN , Manis J , et al. . Plasma cell differentiation requires the transcription factor XBP-1 . Nature . 2001 ; 412 : 300 – 307 . Google Scholar Crossref Search ADS PubMed WorldCat 67. Kamimura D , Bevan MJ . Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection . J Immunol . 2008 ; 181 : 5433 – 5441 . Google Scholar Crossref Search ADS PubMed WorldCat 68. Zeng L , Liu YP , Sha H , et al. . XBP-1 couples endoplasmic reticulum stress to augmented IFN-beta induction via a cis-acting enhancer in macrophages . J Immunol . 2010 ; 185 : 2324 – 2330 . Google Scholar Crossref Search ADS PubMed WorldCat 69. Gatto D , Pfister T , Jegerlehner A , et al. . Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1 . J Exp Med . 2005 ; 201 : 993 – 1005 . Google Scholar Crossref Search ADS PubMed WorldCat 70. Lotz C , Mutallib SA , Oehlrich N , et al. . Targeting positive regulatory domain I-binding factor 1 and X box-binding protein 1 transcription factors by multiple myeloma-reactive CTL . J Immunol . 2005 ; 175 : 1301 – 1309 . Google Scholar Crossref Search ADS PubMed WorldCat 71. Iwakoshi NN , Pypaert M , Glimcher LH . The transcription factor XBP-1 is essential for the development and survival of dendritic cells . J Exp Med . 2007 ; 204 : 2267 – 2275 . Google Scholar Crossref Search ADS PubMed WorldCat 72. Smith JA , Turner MJ , DeLay ML , et al. . Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1 . Eur J Immunol . 2008 ; 38 : 1194 – 1203 . Google Scholar Crossref Search ADS PubMed WorldCat 73. Kaser A , Blumberg RS . Survive an innate immune response through XBP1 . Cell Res . 2010 ; 20 : 506 – 507 . Google Scholar Crossref Search ADS PubMed WorldCat 74. Richardson CE , Kooistra T , Kim DH . An essential role for XBP-1 in host protection against immune activation in C. elegans . Nature . 2010 ; 463 : 1092 – 1095 . Google Scholar Crossref Search ADS PubMed WorldCat 75. Hu F , Yu X , Wang H , et al. . ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells . Eur J Immunol . 2011 ; 41 : 1086 – 1097 . Google Scholar Crossref Search ADS PubMed WorldCat 76. Richardson CE , Kinkel S , Kim DH . Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity. PLoS Genet. 2011 ; 7 : e1002391 . Crossref Search ADS PubMed 77. Yang C , Zhou JY , Zhong HJ , et al. . Exogenous norepinephrine correlates with macrophage endoplasmic reticulum stress response in association with XBP-1 . J Surg Res . 2011 ; 168 : 262 – 271 . Google Scholar Crossref Search ADS PubMed WorldCat 78. Sun J , Liu Y , Aballay A . Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation . EMBO Rep . 2012 ; 13 : 855 – 860 . Google Scholar Crossref Search ADS PubMed WorldCat 79. Kaufman RJ , Cao S . Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism . EMBO Mol Med . 2010 ; 2 : 189 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat 80. Iwakoshi NN , Lee AH , Vallabhajosyula P , et al. . Plasma cell diffeerentiation and the unfolded protein response intersect at the transcription factor XBP-1 . Nat Immunol . 2003 ; 4 : 321 – 329 . Google Scholar Crossref Search ADS PubMed WorldCat 81. Shen Y , Hendershot LM . Identification of ERdj3 and OBF-1/BOB-1/OCA-B as direct targets of XBP-1 during plasma cell differentiation . J Immunol . 2007 ; 179 : 2969 – 2978 . Google Scholar Crossref Search ADS PubMed WorldCat 82. Thorpe JA , Schwarze SR . IRE1alpha controls cyclin A1 expression and promotes cell proliferation through XBP-1 . Cell Stress Chaperones . 2010 ; 15 : 497 – 508 . Google Scholar Crossref Search ADS PubMed WorldCat 83. Zhang K , Wong HN , Song B , et al. . The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis . J Clin Invest . 2005 ; 115 : 268 – 281 . Google Scholar Crossref Search ADS PubMed WorldCat 84. Osorio F , Tavernier SJ , Hoffmann E , et al. . The unfolded-protein-response sensor IRE-1alpha regulates the function of CD8alpha+ dendritic cells . Nat Immunol . 2014 ; 15 : 248 – 257 . Google Scholar Crossref Search ADS PubMed WorldCat 85. Endo M , Mori M , Akira S , et al. . C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation . J Immunol . 2006 ; 176 : 6245 – 6253 . Google Scholar Crossref Search ADS PubMed WorldCat 86. Goodall JC , Wu C , Zhang Y , et al. . Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression . Proc Natl Acad Sci U S A . 2010 ; 107 : 17698 – 17703 . Google Scholar Crossref Search ADS PubMed WorldCat 87. Schreiter K , Hausmann M , Spoettl T , et al. . Glycoprotein (gp) 96 expression: induced during differentiation of intestinal macrophages but impaired in Crohn's disease . Gut . 2005 ; 54 : 935 – 943 . Google Scholar Crossref Search ADS PubMed WorldCat 88. Rosenbaum M , Andreani V , Kapoor T , et al. . MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress . Genes Dev . 2014 ; 28 : 1165 – 1178 . Google Scholar Crossref Search ADS PubMed WorldCat 89. Wang B , Dai S , Dong Z , et al. . The modulation of endoplasmic reticulum stress by chemical chaperone upregulates immune negative cytokine IL-35 in apolipoprotein E-deficient mice . PLoS One. 2014 ; 9 : e87787 . Google Scholar Crossref Search ADS PubMed WorldCat 90. Wirtz S , Billmeier U , McHedlidze T , et al. . Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis . Gastroenterology . 2011 ; 141 : 1875 – 1886 . Google Scholar Crossref Search ADS PubMed WorldCat 91. Gibson DJ , Ryan EJ , Doherty GA . Keeping the bowel regular: the emerging role of Treg as a therapeutic target in inflammatory bowel disease . Inflamm Bowel Dis . 2013 ; 19 : 2716 – 2724 . Google Scholar Crossref Search ADS PubMed WorldCat 92. Boyce M , Bryant KF , Jousse C , et al. . A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress . Science . 2005 ; 307 : 935 – 939 . Google Scholar Crossref Search ADS PubMed WorldCat 93. Treton X , Pedruzzi E , Guichard C , et al. . Combined NADPH oxidase 1 and interleukin 10 deficiency induces chronic endoplasmic reticulum stress and causes ulcerative colitis-like disease in mice . PLoS One. 2014 ; 9 : e101669 . Google Scholar Crossref Search ADS PubMed WorldCat 94. Crespo I , San-Miguel B , Prause C , et al. . Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis . PLoS One. 2012 ; 7 : e50407 . Google Scholar Crossref Search ADS PubMed WorldCat 95. Cao SS , Kaufman RJ . Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease . Antioxid Redox Signal . 2014 ; 21 : 396 – 413 . Google Scholar Crossref Search ADS PubMed WorldCat 96. Zhang K , Kaufman RJ . From endoplasmic-reticulum stress to the inflammatory response . Nature . 2008 ; 454 : 455 – 462 . Google Scholar Crossref Search ADS PubMed WorldCat 97. McGuckin MA , Linden SK , Sutton P , et al. . Mucin dynamics and enteric pathogens . Nat Rev Microbiol . 2011 ; 9 : 265 – 278 . Google Scholar Crossref Search ADS PubMed WorldCat 98. Sheng YH , Hasnain SZ , Florin TH , et al. . Mucins in inflammatory bowel diseases and colorectal cancer . J Gastroenterol Hepatol . 2012 ; 27 : 28 – 38 . Google Scholar Crossref Search ADS PubMed WorldCat 99. Gallo RL , Hooper LV . Epithelial antimicrobial defence of the skin and intestine . Nat Rev Immunol . 2012 ; 12 : 503 – 516 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Reprints: Stewart S. Cao, PhD, Columbia University College of Physicians and Surgeons, 652 W, 163rd Street, New York, NY 10032 (e-mail: sc3676@columbia.edu). The author has no conflicts of interest to disclose. Copyright © 2015 Crohn's & Colitis Foundation of America, Inc.
TI - Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammatory Bowel Disease
JF - Inflammatory Bowel Diseases
DO - 10.1097/MIB.0000000000000238
DA - 2015-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/endoplasmic-reticulum-stress-and-unfolded-protein-response-in-j2VbDhL3sg
SP - 636
VL - 21
IS - 3
DP - DeepDyve
ER -