Intestinal Epithelial Cell Endoplasmic Reticulum Stress and Inflammatory Bowel Disease Pathogenesis: An Update Review
- 1State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing, China
- 2Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, United States
- 3Department of Animal Science, Texas A&M University, College Station, TX, United States
- 4Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
The intestinal epithelial cells serve essential roles in maintaining intestinal homeostasis, which relies on appropriate endoplasmic reticulum (ER) function for proper protein folding, modification, and secretion. Exogenous or endogenous risk factors with an ability to disturb the ER function can impair the intestinal barrier function and activate inflammatory responses in the host. The last decade has witnessed considerable progress in the understanding of the functional role of ER stress and unfolded protein response (UPR) in the gut homeostasis and its significant contribution to the pathogenesis of inflammatory bowel disease (IBD). Herein, we review recent evidence supporting the viewpoint that deregulation of ER stress and UPR signaling in the intestinal epithelium, including the absorptive cells, Paneth cells, goblet cells, and enteroendocrine cells, mediates the action of genetic or environmental factors driving colitis in experimental animals and IBD patients. In addition, we highlight pharmacologic application of chaperones or small molecules that enhance protein folding and modification capacity or improve the function of the ER. These molecules represent potential therapeutic strategies in the prevention or treatment of IBD through restoring ER homeostasis in intestinal epithelial cells.
As the largest barrier that separates the mammalian host from the external environment, gastrointestinal epithelia, including Paneth cells, goblet cells, enteroendocrine cells, and absorptive enterocytes, are critical factors that influence the intestinal homeostasis (1). Specifically, Paneth cells produce and secrete various antimicrobial peptides, which in turn regulate the composition of the intestinal microbiota and the ability to withstand intestinal pathogens (2, 3). Goblet cells are responsible for production of mucins, the predominant component of the intestinal mucus layer that prevents direct contact of luminal contents with epithelial cells (2, 4). The main function of enteroendocrine cells is to produce and secrete peptide hormones that modulate the motility of the digestive tract and metabolism. The absorptive epithelial cells are mainly associated with the secretion of a large number of cytokines and chemokines, which can regulate the composition of the commensal microbiota and the host immune responses (5). Intestinal homeostasis is primarily determined by the appropriate function of the intestinal epithelial cells. Consistently, dysfunction of intestinal epithelium is associated with the development of various gastrointestinal disorders, such as irritable bower syndrome, inflammatory bowel disease (IBD), celiac disease, and mucosal disease (1, 5, 6).
Inflammatory bowel disease, a chronic inflammatory disorder that is mainly composed of Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by abdominal pain, diarrhea, and bloody stools (7–9). Despite well-defined clinical manifestations, the etiology of IBD remains largely unknown. It is generally believed that IBD is a multifactorial gastrointestinal disorder in which various factors, such as genetic factors, intestinal microbiota, host immune responses, and environmental factors are involved (8, 10). Recent studies have shown that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are critical factors associated with susceptibility to IBD and intestinal homeostasis (11, 12). The effect of ER stress on the pathogenesis of IBD is majorly mediated by impairing the mucosal barrier function, regulating innate or adaptive immune response of the host cells, and modulating the intestinal microbiota (13, 14). These findings link ER and IBD, therefore advancing our understanding of IBD pathogenesis and proposing novel therapeutic strategies by restoring ER function in intestinal epithelial cells. Herein, we will review the functional roles of ER in the intestinal homeostasis, and how this homeostasis is impaired by genetic or environmental factors and contributes to susceptibility to IBD. Potential therapeutic interventions targeting ER stress signaling are also reviewed.
The ER and UPR Signaling
The ER is the major site for the synthesis and folding of membrane and secretory proteins (13, 15). In addition, the ER is associated with lipid biosynthesis, energy metabolism, and homeostasis of intracellular Ca2+ (12). Impairment of the ER function causes a cellular condition known as ER stress (16). Mammalian cells have evolved a series of signal transduction pathways to eliminate the deleterious effects, which are collectively termed as the UPR. Activation of UPR is an adaptive response for mammalian animals to restore ER homeostasis and survive the stressful conditions by blocking global mRNA translation, eliminating misfolded proteins by ER-associated protein degradation (ERAD) signaling pathway, and enhancing the capacity for protein folding and modification (16, 17). However, severe or prolonged ER stress can activate cell death signaling to remove damaged cells (12, 18, 19).
In eukaryotic cells, UPR signaling pathways are mainly mediated by three protein sensors on the ER membrane: inositol-requiring transmembrane kinase/endonuclease 1 (IRE1), pancreatic ER eIF2α kinase (PERK), and activating transcription factor 6 (ATF6) (20–22) (Figure 1). Under non-stressed conditions, all three transmembrane sensors are bound to the ER chaperone binding immunoglobulin protein (Bip, also known as glucose-regulated protein 78) in their intraluminal domains and are maintained in an inactive state (23–25). Upon ER stress, Bip dissociates from the luminal domains of the three protein sensors, therefore activating IRE1, PERK, or ATF6, and initiating UPR and downstream cascade signaling (26, 27).
Figure 1. Three signaling pathways of unfolded protein response (UPR). Under homeostatic conditions, immunoglobulin heavy chain-binding protein (Bip) binds and inhibits the three transmembrane proteins of UPR: the inositol-requiring transmembrane kinase/endonuclease 1 (IRE1), the pancreatic endoplasmic reticulum (ER) kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Under ER stress conditions, Bip dissociates from the three transmembrane proteins and binds to the misfolded or unfolded proteins in the ER, which activates IRE1, PERK, and ATF6 downstream signalings. Once released from Bip, IRE1 is activated through homodimerization and trans-autophosphorylation. The activated IRE1 slices the X-box binding protein (XBP1u) and generates a functionally active isoform of XBP1 (XBP1s). XBP1s is a transcription factor that modulates the expression of genes encoding ER chaperones, ER-associated protein degradation (ERAD) members, ER translocases, glycosylases, disulfide isomerases, and components involved in lipid biosynthesis. IRE1 also binds to and activates TNFα receptor associated factor 2 (TRAF2), which results in activations of c-Jun N-terminal kinase (JNK), therefore contributing to inflammatory, proapoptotic signaling in response to the ER stress. PERK is also activated by homodimerization and trans-autophosphorylation. Activated PERK phosphorylates the eukaryotic translation initiation factor 2 (eIF2α), thereby attenuating global protein synthesis and alleviating the burden on ER. However, the transcription factor ATF4 can bypass the inhibition and activate the expression of Chop, which is a master regulator of ER stress-induced apoptosis. After disassociation from ATF6. Bip moves to the Golgi apparatus, where it subsequently undergoes intramembrane proteolysis in its luminal domain. The released ATF6 fragment (ATF6f) translocates to the nucleus and regulates the expression XBP1, Bip, P58IPK, and Chop.
Among the three protein sensors, IRE1 is the most evolutionarily conserved ER stress transducer protein (20, 28). IRE1 exists in two structurally related isoforms, IRE1α, the ubiquitously expressed isoform, and IRE1β, which has been primarily identified in the intestinal epithelium of the gut and respiratory tract (29, 30). Upon sensing the misfolded or unfolded proteins, Bip protein dissociates from IRE1α and facilitates the activation of IRE1α through homodimerization and trans-autophosphorylation or other mechanisms (31, 32). Activated IRE1α uses its endoribonuclease activity to remove a 26-bp pair segment from an unspliced mRNA encoding the transcription factor X-box binding protein 1 (XBP1u), which in turn causes a shift in the reading frame and generates a spliced and functionally active isoform of XBP1 (XBP1s) (33, 34). XBP1s is a potent CREB/ATF basic leucine zipper (bZIP) transcription factor that can induce the expression of genes involved in protein folding, secretion, maturation, the ERAD signaling and the synthesis of phospholipids (26, 35). Several lines of studies have shown that XBP1s is also implicated in various biological processes, such as lipid metabolism (36), pro-inflammatory cytokines synthesis (37), the hypoxia response signaling pathway (38), cellular differentiation (39), and the hexosamine biosynthetic pathway (40), indicating a critical role for IRE1-XBP1 UPR signaling and cellular response. Unlike XBP1s, XBP1u is a short-lived protein that lacks the transactivation domain. XBP1u inhibits the translocation of XBP1s from cytoplasm into the nucleus, therefore serving as a dominant-negative regulator to block the transactivation of XBP1 downstream targets under certain conditions (41–43). Recent studies have shown that IRE1α can target other mRNAs for degradation, therefore inhibiting the synthesis of nascent proteins through the regulated IRE1-dependent decay (19, 44, 45), indicating an additional level of regulation to cope with ER stress.
It should be noted that the functional role of IRE1α on various biological processes, such as proliferation, metabolism, inflammation, autophagy, and apoptosis, can be mediated in an XBP1-independent manner (46). First, IRE1α can bind to and activate TNFα receptor associated factor 2 in the cytoplasm, which in turn activates c-Jun N-terminal kinase or nuclear factor-κB (NF-κB), thus participating in inflammatory response or proapoptotic signaling in response to ER stress (12, 17, 18). Second, IRE1α can directly modulate p38 MAPK and ERK1/2, two critical protein kinases related to stress response, indicating a link between UPR signaling and cellular response (47). Third, IRE1α has been reported to interact with the proapoptotic BCL-2 (B-cell lymphoma 2) family proteins, BAX (BCL-2-associated X protein), or BAK (BCL-2 antagonist/killer), therefore contributing to apoptotic cell death (48). In addition to transcription regulation and protein interactions, IRE1α can cause degradation of selective microRNA that normally represses translation of caspase-2, therefore leading to activation of the mitochondrial apoptosis pathway (49–51). More studies are required to elucidate how this epigenetic regulation is implicated in and contribute to intestinal homeostasis. In contrast to IRE1α, IRE1β has a broader endoribonuclease activity, which can lead to the degradation of a large array of transcripts (52). However, the underlying mechanisms are incompletely understood.
PERK has structural similarities with IRE1 transmembrane protein (21, 53). Disengagement from Bip upon sensing misfolded or unfolded protein in the ER activates PERK by homodimerization and trans-autophosphorylation (11, 54, 55). Activated PERK phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), a component of the translation initiation complexes, therefore attenuating global protein synthesis and alleviating the overload of misfolded proteins (53, 56). Interestingly, the phosphorylated eIF2α selectively enhances translation of ATF4, a transcription factor regulating the expression of genes implicated in protein folding, oxidative stress response, and ER stress-induced apoptosis (57, 58). CHOP (CCAAT/enhancer-binding protein homologous protein, also known as GADD153) has been shown to be a critical mediator responsible for ER stress-induced cell death through different mechanisms (19, 59). First, CHOP can suppress the antiapoptotic protein BCL-2 or enhance numerous proapoptotic proteins, such as Bim, telomere repeat binding factor 3, GADD34 (growth arrest and DNA damage 34), or death receptor 5 (60–62). Second, CHOP induces the transcriptional expression of ER oxidase 1α, which in turn resulted in generation of reactive oxygen species (ROS) and release of Ca2+ from the ER, thereby conferring to apoptosis (12, 18, 19). Third, CHOP can interact with ATF4 and activate genes involved in protein synthesis machinery, thus causing energy depletion and apoptosis in ER-stressed cells (63). In addition to inducing cell death, activation of the PERK pathway can activate antioxidant reactions to avoid accumulation of ROS in response to ER stress (64). This effect of PERK is mediated by ATF4-induced phosphorylation of nuclear factor-erythroid-derived 2-related factor 2, which can activate enzymes with an ability to remove oxidants. These enzymes include NAD(P)H-quinone oxidoreductase, heme oxygenase 1, and glutathione S-transferase (65, 66).
Besides PERK, eIF2α can be phosphorylated by other protein kinases, including PKR (double-stranded RNA activated protein kinase) (67), general control non-depressive kinase 2 (68), and heme-regulated inhibitor kinase (69). All the protein kinases have similar kinase catalytic domains, and therefore possess a capability to phosphorylate eIF2α at its Ser 51 residue to regulate protein synthesis (70). Because of the presence of different regulatory domains in the kinases, they can be activated by different stress stimuli (70). Despite the diversity of stress stimuli and activated protein kinases, these signaling cascades converge on the phosphorylation of eIF2α, indicating a critical functional role of eIF2α in determining cell fate decision. These biochemical roles of eIF2α have been highlighted in several review papers (70, 71). Additional studies are needed to elucidate how the kinases-activate eIF2α interacts with ER stress signaling and contribute to cell survival and apoptosis under specific conditions.
Importantly, eIF2α can be dephosphorylated by protein phosphatase, such as protein phosphatase 1 regulatory subunit 15A (growth-arrest DNA damage-inducible protein 34, also known as GADD34) and subunit 15B (known as CReP) (72–74), thus forming a negative feedback regulation on PERK–eIF2α signaling. All these data indicate that activation of eIF2α acts as a molecular switch either to induce cell death or to promote cell survival by attenuating protein synthesis in a context-dependent manner (63).
Activating transcription factor 6 is a key transcription factor that helps intestinal epithelial cells cope with ER stress (22). Two homologous ATF6 proteins, such as ATF6α and ATF6β, have been identified in mammalian cells (75). Upon sensing the misfolded or unfolded proteins in the ER, ATF6 that is released from Bip migrates from the ER to the Golgi apparatus, where it subsequently undergoes cleavage by site-1 protease (S1P) and site-2 protease (S2P) in its luminal domain and transmembrane region, respectively, leading to the release of the cytosolic domain of ATF6, ATF6 fragment (ATF6f) (22, 24). ATF6f then translocates to the nucleus to bind DNA and transcriptionally upregulates target genes involved in protein folding, or ERAD to restore ER homeostasis or induce cell death in response to severe or prolonged ER stress (76–79).
In addition to the canonical ER membrane-bound proteins, IRE1, PERK, and ATF6 as abovementioned, novel types of ER stress transducers sharing a region of high sequence similarity with ATF6 have been identified (80, 81). These proteins possess a transmembrane domain, which allows them to associate with the ER, and have a transactivation domain and a basic leucine zipper (bZIP) domain. They are collectively known as old astrocyte specifically induced substance (OASIS) family members, which consist of CREB3L1/OASIS (82), CREB3L4/CREBH (RE-Bip H) (83), CREB3L2/BBF2H7 (box B-binding factor 2 human homolog on chromosome 7) (84), AIbZIP/Tisp40/CREB3L4/CREB4 (cyclic AMP responsive element Bip 4) (85), and Luman/LZIP/CREB3 (86, 87). Most of these ATF6-related bZip factors are processed at the Golgi as described for ATF6, but their functions are tissue specific due to the unique cell or tissue specific expression patterns of these transducers (88, 89).
Intestinal Epithelial cell and ER Stress in IBD
The gut epithelial cells are constantly exposed to a complex microenvironment involving intestinal microbiota, antigens, dietary metabolites, and bacterial toxins (90). Among the epithelial cells, enterocytes are the major cell types that are replaced in a short period, which require a high metabolic rate and biosynthesis of large amounts of proteins, cytokines, and small peptides. As the major secretory cells, goblet cells and Paneth cells can produce and secret mucin glycoproteins which are the major components of mucus that separate the luminal microbial flora from the intestinal epithelium and lubricates the epithelium (4, 91). They can also secrete defensins, lysozymes, antimicrobial lectins, collectins, and smaller amounts of MUC2 (2, 92). Under physiological conditions, the secretion of antimicrobial peptides and mucins with large numbers of disulfide bonds and/or homo-oligomerization can be maintained in homeostasis due to appropriate ER function in intestinal epithelium (90, 92). In response to environmental factors, such as pathogenic bacteria infection, the production of MUC2 or defensins can be stimulated in the secretory cells (93, 94), thus exerting a significant protein folding and modification burden on ER in IECs. This burden and the complexity of the intestinal environment may pose particular challenges to the capacity of proteins for folding in intestinal epithelial cells and results in ER stress and activation of UPR survival signaling or induction of cell death if the ER homeostasis could not restored (95). In addition, ER stress in intestinal epithelial cells is associated with activation of host immune response and intestinal dysbiosis, which are critical factors implicated in the pathogenesis of intestinal diseases including IBD and mucosal disease (14, 90, 96). Importantly, a genetic deficiency of genes involved in UPR results in higher susceptibility to IBD due to decreased capacity to reduce the concentrations of unfolded proteins in the ER, as well as overactivated immune response in epithelial cells (55, 97–99) (Table 1).
Table 1. Role of endoplasmic reticulum stress and secretion-related genes in inflammatory bowel disease.
UPR Regulators and IBD Pathogenesis
IRE1/XBP1 Signaling in IBD
Initial evidence linking IRE1/XBP1 signaling to intestinal inflammation came from a study showing that genetic deletion of IRE1β increased the protein level of Bip in the colonic mucosa and susceptibility to dextran sodium sulfate (DSS), a well-known inducer of experimental colitis in mice (30). Further study has shown that IRE1β knockout mice exhibit impaired intestinal barrier function and aberrant accumulation of mucin due to the deficiency of the negative feedback control on mucin by IRE1β in goblet cells (100). Similarly, genetic deletion of IRE1α in IECs leads to spontaneous colitis, which is accompanied by loss of goblet cells and dysregulated epithelial barrier function (101). Moreover, IRE1α−/− mice are more susceptible to DSS-induced colitis and ER stress-related apoptosis (101). XBP1 is a critical effector transcription factor of IRE1 signaling in response to ER stress and unfolded protein accumulation. It is not a surprise that the XBP1 gene on chromosome 22q12 has been linked to IBD for more than two decades (102, 103). The deep sequencing of Xbp1 and its promoter revealed more single nucleotide polymorphisms (SNPs) in both UC and CD patients than in healthy controls (97). These SNPs in Xbp1 were found to be associated with decreased transactivation of XBP1-regulated UPR target genes and increased inflammatory response. The functional role for XBP1 in IBD was further validated in Xbp1−/−(IEC) (genetic depletion of Xbp1 in the epithelium of the small and large intestines) mice, as evidenced by spontaneous development of intestinal inflammation and increased sensitivity to DSS (97). Moreover, Xbp1−/−(IEC) mice have leaky intestinal barrier, increased translocation of invading pathogens to the liver and other tissues, indicating an essential role of Xbp1 in the intestinal homeostasis and host immune response, which might act in concert and contribute to IBD (97).
PERK/CHOP Signaling in IBD
CHOP is a transcription factor implicated in both apoptosis and inflammatory responses (104). Elevated expression of CHOP has been observed in the intestinal epithelium of IBD patients and mice with deficiency in Xbp1, Atf6α, or P58IPK (11, 97). Park et al. reported that ER stress-activated CHOP can suppress peroxisome proliferator-activated receptor γ, a negative regulator of NF-κB, therefore resulting in NF-κB activation (105). Activated NF-κB translocates into the nucleus and enhanced the production of interleukin-8, a pro-inflammatory cytokine in intestinal epithelium, which in turn contributes to intestinal dysfunction and IBD (105). In addition to a regulatory effect on cytokines, CHOP can promote the infiltration of macrophages, induce ROS and IL-1β production, or enhance apoptosis of epithelial cells, thus leading to the development of colitis (106).
In addition to IL-8 and IL-1β, interleukin 23 (IL-23) has been identified as a critical cytokine in the pathogenesis of IBD (107). Polymorphisms in IL-23 receptor (IL-23R) have been reported in both CD and UC patients (108). Further study shows that IBD-affected individuals have an increased concentration of IL-23 in the inflamed epithelium, indicating a potential role for IL-23 in intestinal immune response (109). The pro-inflammatory activity of IL-23 has mostly been linked to its effect on Th17 cells, a population of T cells characterized by the production of the inflammatory cytokine interleukin 17 (IL-17) (110). The functional role for the IL-23/IL-17 axis in intestinal inflammation has been validated in various animal models (110, 111). In addition, IL-23 can also regulate the activity of regulatory T cells, therefore modulating the host immune system (112–116). In a recent study, the CHOP protein has been reported to enhance TLR-induced IL-23 production by enhancing the binding to the IL-23 p19 (Il23A) promoter in ER-stressed myeloid cells (117). Further study is needed to explore whether this transcriptional regulation is implicated in and contributes to intestinal inflammation.
ATF6 Signaling in IBD
An appropriate function of ATF6α is required to survive chemical-induced ER stress in mice (118). This effect of ATF6α is mediated by transcriptional activation of ER chaperone genes, including Bip, Grp94, and P58IPK (64, 119, 120). ATF6α knockout (Atf6α−/−) mice display reduced expression of ER chaperone genes, and increased expression of a proapoptotic protein CHOP in colonic epithelium (11). P58IPK knockout mice have a decreased number of goblet cells, increased inflammatory cell infiltration, and more severe mucosal damage upon DSS challenge (11). These data highlight the requirement of ATF6 signaling for intestinal barrier function and inflammatory response.
The functional role of ATF6 signaling pathway in the pathogenesis of IBD has been revealed by the using of mice with mutations in Mbtps1, a gene encoding ATF6 activator S1P (121). These mice exhibited decreased protein levels of Bip, Grp94, and impaired ATF6-driven UPR to DSS administration (121). It should be noted that S1P can also activate OASIS, a bZIP transcription factor implicated in colitis by interfering with ER stress signaling (122). Moreover, Oasis−/− mice have been reported to have similar phenotypes to those observed in ATF6 knockout mice, including impaired goblet cell function (123), and elevated apoptotic proteins in IECs (124). It is currently unknown which signaling pathway is a major contributor to the development of chemical-induced colitis in Mbtps1 deficiency mice. Additional studies with genetically engineered mice are needed to answer this question and a potential functional overlap between ATF6 and OASIS signaling.
Protein Secretion-Related Factors in IBD
Paneth cells and goblet cells in the gastrointestinal tract can produce large amounts of proteins, which undergo protein folding and posttranslational modifications before being secreted from the cells (90, 92). This feature of secretory cells requires a fine monitoring and management of the ER to avoid the accumulation of unfolded or misfolded proteins. Both clinical and experimental animal studies show that impaired UPR is associated with development of colitis in humans and animals as abovementioned (11, 100, 123). Several lines of studies show that dysfunction of genes involved in protein secretion, such as Anterior gradient 2 (Agr2) and MUC2, is associated with IBD through various mechanisms (98, 125).
Agr2 is an ER-resident protein expressed in secretory IECs such as goblet, Paneth, and enteroendocrine cells in the small intestine (126). This protein responsible for the formation of correctly arranged disulfide bonds in mature proteins (127, 128). By using inducible Agr2−/− mice, Fang et al. showed that deletion of Agr2 is associated with decreased goblet cells and MUC2, dramatic expansion of the Paneth cell compartment, abnormal Paneth cell localization, elevated ER stress, and severe colitis (125). This finding, along with previous observation that both CD and UC patients have decreased AGR2 (129), indicates that AGR2 is essential for intestinal homeostasis. Deficiency of this gene impairs the secretion of proteins in intestinal epithelial cells and activates uncontrolled immune response, ultimately contributing to IBD.
MUC2 is the major component of mucin that goblet cells secrete into the intestinal lumen (130, 131). An appropriate secretion of MUC2 requires extensive O-glycosylation of central mucin repeats and intra- and inter-chain disulfide bond formation in the cysteine-rich N and C-terminal domains within the ER (132). Mutations in the Muc2 gene lead to ER stress, inflammation, and spontaneously colitis due to accumulation of MUC2 precursor in the ER and reduction in mucin secretion (98). Similar observations have been described in UC patients (131, 133). Interestingly, administration of interleukin-10 (IL-10), an anti-inflammatory cytokine, has been reported to attenuate intestinal inflammation and enhance mucin production in ER-stressed epithelial cells through currently unknown mechanisms (99).
Environmental Factors and ER Stress Signaling in IBD
Besides the genetic factors and secretion-related proteins, various environmental factors have been implicated in ER stress signaling and contribute to intestinal inflammation in IBD (99, 134–136). Several inflammatory mediators have been shown to be able to influence ER stress response. For example, anti-inflammatory cytokine IL-10 can modulate ATF6 nuclear recruitment to the Bip promoter, therefore blocking ER stress (99). This finding provides a plausible explanation for the development of colitis in IL-10 knockout mice (137). By contrast, pro-inflammatory cytokine tumor necrosis factor α (TNF-α) can enhance ER stress and UPR signaling by inducing ROS production and its accumulation in the ER (134). Moreover, increased expression of inflammatory cytokines, such as IL-1β, TNF-α, and IFN-γ, has been observed in aberrant mucin assembly induced colitis mice (98). These findings highlight a role of immune response in the development of experimental colitis or IBD. More studies are required to uncover how the antagonistic cytokines are finely coordinated under physiological conditions and ER-stressed conditions.
Intestinal microbiota is considered to be another environmental factor highly correlated with IBD (138, 139). Intestinal microbiota is well known to produce inflammatory molecules by regulating expression of genes involved in immune response, which in turn triggers ER stress (55). In addition, the effect of microbiota on ER stress can also be mediated by various microbial metabolites. For example, trierixin, a macrocyclic lactam derived from Streptomyces sp., has been identified as an inhibitor of XBP1 splicing (135). Interestingly, two structurally related compounds, such as mycotrienin II and trienomycin A, were isolated from the culture broth of a trierixin-producing strain and reported to inhibit the induction of XBP1 (135). These compounds might be potential pharmacological tools for the functional analysis of XBP1 signaling in response to ER stress. However, key enzymes involved in the production of these metabolites with an ability to suppress XBP1, as well as their effects on the intestinal homeostasis, are still largely unknown. Paton et al. reported that oral infection with AB5 a cytotoxin-producing Escherichia coli resulted in pathologic UPR in mice (136). Further studies showed that the A subunit of AB5 cytotoxin specifically cleaved Bip by the serine protease activity and activated it in eukaryotic cells (140). Notably, proteins with significant sequence homology to the A and B subunits of this cytotoxin have been reported in a wide variety of microorganisms (136), which can interfere with the ER stress-related signaling cascade and inflammatory responses in the IECs.
ER Stress and UPR in IBD Therapeutics
Therapies for IBD are faced with extraordinary challenges due to limited understanding of its etiology and pathogenesis (141). Experimental and clinical data have shown that deregulated ER stress signaling in intestinal epithelial cells is associated with development of UC or CD. In this scenario, chemical drugs or small molecules with the ability to reduce unfolded proteins or enhance the capacity of ER for protein folding and modification might be potential therapeutic strategies to prevent or treat IBD. Tauroursodeoxycholic acid (TUDCA), a bile acid derivative, and 4-phenylburyrate have been reported to enhance protein folding, ameliorate ER stress, and enhance insulin sensitivity in liver and muscle of obese patients (142–145). In a recent study, Cao et al. showed that oral administration of these two compounds dramatically alleviated DSS-induced inflammation and colitis via abolishing ER stress signaling in colonic IECs (11). A structure–function analysis revealed that ursodeoxycholic acid, the unconjugated form of TUDCA, is 10 times more effective in alleviating ER stress than TUDCA in IECs (146), and might be a potential drug to alleviate ER stress related colitis. It should be noted that this result is based on cell free assay; in vivo studies involving animals and clinical patients are required to validate this preliminary result. In another study, vaticanol B, a resveratrol tetramer, has been shown to suppress the induction of Bip, CHOP, and the secretion of TNF-α, indicating a beneficial effect by improving the ER function and maintaining the membrane integrity of the ER (147). In addition, fexofenadine, an antihistamine agent for allergic rhinitis and urticaria (148), has been found to prevent DSS-induced colitis by blocking ER stress-induced eIF2α and inhibiting NF-κB signaling in IECs through a histone receptor-independent signaling (149). Salubrinal, a specific inhibitor of eIF2α dephosphorylation, was found to ameliorate experimental colitis by boosting adaptive UPR signaling Bip, ATF4, and heat-shock protein 70 (150, 151). In addition to the chemical chaperones, nutritional interventions have gained increasing attention due to their regulatory effects on expression of genes implicated in ER stress. Glutamine, an abundant amino acid in tissues, has been reported to ameliorate 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis by abrogating ER stress, reducing oxidative injury, attenuating apoptosis and the inflammatory response in colonic epithelial cell, and highlighting a potential nutritional strategy to restore ER function and improve intestinal homeostasis (152). In our recent study, we found that glutamine can regulate tight junction protein permeability through calcium/calmodulin-dependent kinase kinase 2 signaling in intestinal porcine epithelial cells (153). These findings suggest that supplementation with glutamine might be a promising adjuvant in IBD therapeutics. Considering that most of these data are results from in vitro or animal models. Further studies for the underlying mechanisms and clinical efficacy are warranted before these molecules can be used as a novel therapeutic option in IBD patients.
Endoplasmic reticulum stress and related UPR signaling are implicated in and contribute to the initiation or progression of IBD. The last decade has witnessed considerable progress in the understanding of ER stress and UPR signaling in maintaining intestinal homeostasis. Dysfunction of the ER triggered by various factors is associated with susceptibility to of CD and UC and impairment in intestinal barrier. Reestablishing intestinal homeostasis by correcting ER stress-related signaling network is emerging as a potential therapeutic target for IBD. Considering that protein folding, posttranslational modification and trafficking are fundamental biological processes implicated in various physiological and pathological processes, manipulation of ER stress signaling without causing severe side effects is a challenge that must be carefully considered before its recommendation for the treatment of IBD patients. IBD is a chronic and relapsing inflammatory condition of the gastrointestinal tract, in which genetic factors, environmental factors, as well as an interplay between intestinal microbiota and the host immune response, contribute to the pathogenesis of the disease. An ideal therapy for IBD that is tailored to an individual’s specific condition highly depends on a deep understanding of phenotype, natural history, and the pathogenesis of this disease.
GW and ZW designed the study; XM, YZ, YY, and JC contributed to the literature search; XM, KS, and ZD drafted the manuscript; ZW, PT, and GW revised and finalized the manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the National Basic Research Program of China (No. 2013CB127302), the National Natural Science Foundation of China (No. 31572423, 31272450, 31572412, 31272451, 31572410, 31625025, and 31372327), the Chinese Universities Scientific Fund (2015DK001), the Program for New Century Excellent Talents in University (NCET-12-0522), and the “111” Project (B16044).
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Keywords: intestinal epithelial cells, unfolded protein response, endoplasmic reticulum stress, immune response, intestinal bowel disease, colitis
Citation: Ma X, Dai Z, Sun K, Zhang Y, Chen J, Yang Y, Tso P, Wu G and Wu Z (2017) Intestinal Epithelial Cell Endoplasmic Reticulum Stress and Inflammatory Bowel Disease Pathogenesis: An Update Review. Front. Immunol. 8:1271. doi: 10.3389/fimmu.2017.01271
Received: 04 August 2017; Accepted: 25 September 2017;
Published: 25 October 2017
Edited by:Junji Yodoi, Kyoto University, Japan
Reviewed by:Sinisa Savic, University of Leeds, United Kingdom
Nicolas Riteau, National Institutes of Health (NIH), United States
Copyright: © 2017 Ma, Dai, Sun, Zhang, Chen, Yang, Tso, Wu and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhenlong Wu, firstname.lastname@example.org