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Khan, Mohammad Moshahid*; Yang, Weng-Lang*,†; Wang, Ping*,†

doi: 10.1097/SHK.0000000000000425
Review Article

ABSTRACT Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle, is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under stress and inflammatory conditions, ER loses homeostasis in its function, which is termed ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once stress is beyond the compensatory capacity of UPR or protracted, apoptosis would be initiated by triggering cell injuries, even cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidence that ER stress participates in the pathogenesis of sepsis. In this review, we summarize current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma-hemorrhage and ischemia/reperfusion injury. We also discuss the potential implications of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.

*Center for Translational Research, The Feinstein Institute for Medical Research

Department of Surgery, Hofstra North Shore–LIJ School of Medicine, Manhasset, New York

Address reprint requests to Ping Wang, MD, Center for Translational Research, Feinstein Institute for Medical Research, 350 Community Dr. Manhasset, NY 11030. E-mail:

Received 21 April, 2015

Revised 7 May, 2015

Accepted 5 June, 2015

This study was supported by the National Institutes of Health (grant no. R01GM053008 and grant no. R01GM057468 to P.W.).

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Sepsis and septic shock are serious health care issues, resulting from a severe inflammatory response to infection and injury that leads to multiple organ failure (1–3). Sepsis progresses quickly, and the general public is “little” aware of its threat. Sepsis is referred to as an “equal-opportunity” threat because it does not respect the age, sex, race, or economic status of its victims and has been a scourge of the human race for thousands of years. It is estimated that 18 million cases of sepsis occur each year in the world, with mortality rates ranging as high as 30% to 50% (4). Those septic patients who initially survive experience functional deficits and impaired quality of life, in addition to being at risk for higher mortality. In the United States, the annual cost of providing care to septic patients is approximately $24 billion (5,6). Currently, there is no effective therapeutic intervention against sepsis approved by the US Food and Drug Administration. In the past 30 years, there has only been one US Food and Drug Administration–approved medicine (i.e., activated protein C or Xigris), but it was voluntarily withdrawn in 2011 by the manufacturer because follow-up studies did not show substantial improvement in the survival of septic patients (7). Understanding the biological process involved in the pathogenesis of sepsis is an important first step in improving outcomes and treating patients.

The endoplasmic reticulum (ER) is a vital intracellular organelle in the secretory pathways, commonly known as the protein folding factory(8–10). It is responsible for protein translocation, protein folding, and protein posttranslational modifications that allow further transport of proteins to the Golgi body. Moreover, ER provides the place for calcium storage, lipid synthesis, and carbohydrate metabolism. Certain pathological conditions, such as sepsis, trauma, ischemia, and viral infection, as well as few pharmacological agents including tunicamycin, thapsigargin, and brefeldin A, lead to the accumulation of unfolded or misfolded proteins that alter the homeostasis of the ER and cause ER stress (11–14). The ER is equipped with three superspecialized sentinel ER membrane–embedded proteins named inositol-requiring protein 1 (IRE1), double-stranded RNA-dependent protein kinase–like ER kinase (PERK), and activating transcription factor 6 (ATF6) to sense the stress in the ER (15–18). When these sensors recognize the enhanced ER stress, the ER elicits a sophisticated and complex adaptive response, referred to as unfolded protein response (UPR) to rebuild cellular homeostasis (16,19–21). The aim of these signaling cascades is to reduce the accumulation of unfolded proteins in the ER; however, when these events are unresolved or protracted, it initiates apoptosis and other components of cell death (8,10,22,23).

There is growing interest in investigating the regulatory mechanisms underlying ER stress and UPR signaling and the development of strategies to target this pathway because there is substantial evidence for the participation of ER stress in many diseases, including inflammatory disorders, neurodegeneration, cancer, and diabetes (18,24–26). Interestingly, attenuation of ER stress with pharmacological or gene therapy strategies has been successful in reducing pathological features in various experimental models of inflammatory diseases (14,24,27,28). Thus, we demonstrate that investigations on ER stress will hold promise to reveal novel therapeutic targets for inflammatory diseases including sepsis in humans. This review highlights recent progress toward the understanding of the role of ER stress in sepsis and its related clinical conditions. Specifically, we focus on the possible implications of ER stress and its constituents in sepsis, trauma-hemorrhage, and ischemia/reperfusion (I/R) injury and the potential use as prognostic markers and a novel therapeutic target under these clinical conditions.

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ER stress and UPR: An overview

The ER is a complex network of tubules and flattened sacs that have a variety of physiological functions in the cell. The ER serves a role in adequate folding of nascent proteins and transport of synthesized proteins to the Golgi body. To ensure proper protein folding, the ER maintains a unique environment by several ER-related genes (Table 1) to establish a balance between the ER protein load and the ability to control this load. The proper folding of protein within the cell is mediated by several ER-bounded chaperone proteins, including protein disulfide isomerase, the Hsp70 family member glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (Bip), calnexin, and calreticulin (15,16,18). Disturbances in redox regulation, inflammatory overloads, calcium homeostasis, or the overexpression of protein can lead to impairment of this protein folding machinery, and this condition is referred to as ER stress. To protect against such kinds of stress, cells have an orchestrated and integrated UPR signaling to restore homeostasis and normal ER function. As a consequence, 1) ER sensors diminish the protein load by inhibiting protein translation and by limiting the pool of mRNAs ready to process in the ER, 2) induction of ER chaperones for proper folding of nascent proteins and allowing them to translocate into the Golgi body, 3) and activation of ER-associated degradation (ERAD) machine to trap the unfolded proteins (Fig. 1). However, if this signaling cascade is insufficient to restore the ER homeostasis and cellular function is compromised, apoptosis is initiated (8,18,19).

Table 1

Table 1



The UPR is a double-edged sword; it confers cytoprotection when activated to a moderate extent but becomes a threat when it is protracted over and may lead to cellular dysfunction, death, and disease. The UPR consists of two central components, a group of specialized stress sensors IRE1, PERK, and ATF6 located in the ER membrane and downstream transcription factors eIF2-α (for PERK), fragmented ATF6 (for ATF6), and spliced XBP1 (for IRE1) that reprogram gene expression to enable adaptation to stress or the induction of apoptosis depends on the severity and extent of the damage. These factors directly activate the transcription of chaperones or proteins functioning in redox homeostasis, protein secretion, lipid biosynthesis, autophagy, inflammation, or cell death programs (Fig. 2).



Under conditions of prolonged ER stress, UPR sensors shift their signaling toward cell death possibly through distinct overlapping signaling mechanisms. The first is transcriptional activation of the gene for C/EBP homologous protein (CHOP) mediated by PERK, IRE1, and ATF6 (35,36). The second is activation of the c-Jun N-terminal protein kinase (JNK) pathway, which is mediated by IRE1 and subsequent activation of TNF receptor–associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) (37). The third is activation of ER-associated caspase-12 activation (38,39). Activated caspase-12 is a representative caspase implicated in cell death–executing mechanisms corresponding to ER stress (40). During prolonged ER stress, caspase-12 migrates from the ER to the cytosol and cleaves caspase-9 and further activates caspase-3. A study by Nakagawa et al. (40) reported that caspase-12–deficient mice were resistant to amyloid-beta–induced apoptosis in an experimental model of Alzheimer disease and proposed that murine caspase-12 serves as a key mediator of ER stress and suggested a human ortholog of caspase-12 as a potential therapeutic target.

Thus, ER is an organelle of great importance. The UPR pathway is valuable for cellular homeostasis and other important physiological activities. Therefore, investigating the UPR pathway and monitoring ER stress in experimental model systems are important to study the pathogenic mechanisms associated with sepsis and other related clinical conditions in humans. Nevertheless, it is also worth investigating to measure the stress in other organelles as well as during pathological conditions.

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ER stress and UPR signaling

There are three types of UPR signaling associated with ER stress, which control the expression of specific transcription factors and UPR downstream pathways. Here, we explain the ER stress–mediated UPR signaling and discuss the possible mechanisms involved in the transition of the UPR from a protective to a proapoptotic phase during prolonged ER stress in disease conditions.

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IRE1 and XBP1 axis

The IRE1/XBP1 axis has been documented as the conserved core of the UPR, which largely exists from yeast to human and is essential for mammalian developmental processes (13). The IRE1 is an ER membrane protein whose ER domain is involved in the sensing of unfolded or misfolded proteins, whereas the cytoplasmic domain serves as a protein kinase and in endoribonuclease activities. Two different isoforms of IRE1 have been presented in mammalian cells: IRE1α and IRE1β. The IRE1α is ubiquitously expressed, whereas IRE1β is tissue specific—mostly localized in the gut (41). Accumulation of unfolded proteins in the ER results in the release of bound GRP78 from IRE1, stimulates IRE1α oligomerization in the ER membranes, and autophosphorylation of the IRE1α cytosolic domain (15,42). Activated IRE1 splices a 26-nucleotide intron from the mRNA encoding XBP1, which generates a more stable and potent transcriptional factor of UPR genes, known as spliced XBP1(43). The XBP1 s target genes and downstream effects are cosmopolitan, depending on the cell type and the nature of the stress stimuli.

The XBP1 protein binds to promoters of several genes involved in UPR and ERAD to restore protein homeostasis and provide cytoprotection. Deficiency of XBP1 has been shown to result in the impairment of pancreatic cells, hepatocytes, and plasma B cells, all of which produce large amounts of secretory proteins, suggesting an important role for XBP1 in preserving the protein secretory machinery. In addition, the XBP1 s indirectly regulates the biogenesis of the ER and Golgi by enhancing the activity of enzymes related to phospholipid biosynthesis (44). The XBP1 s also binds estrogen receptor-α in a ligand-independent manner (45). However, the relevance of these interactions remains unclear. Recent studies identified an interaction between the p85α regulatory subunit of phosphatidylinositol 3-kinase and XBP1 s in an ER stress–dependent manner (46,47). This association is linked with the regulation of metabolic control in diabetes (48). In addition, XBP1 s was documented to negatively regulate the expression levels of the transcription factor Forkhead box O1, which also modulates glucose metabolism (49). Moreover, a study by Ye et al. (50) demonstrated that TLR4 promotes liver disease by inducing reactive oxygen species (ROS)–dependent XBP1 activation in Kupffer cells, suggesting the role of XBP1 in the immune response. Discrepancies in the role of XBP1 in immune response reflects the multifaceted function and in regulation of its target gene. This is an active area of research, and recent works have begun to uncover the precise mechanisms by which IRE1α governs these pathways.

Inositol-requiring enzyme-1α controls the initiation of several downstream signaling pathways in addition to the processing of XBP1 mRNA. In addition to endoribonuclease, activated IRE1 also serves as a kinase and binds to TRAF2, which recruits ASK1 and activates the phosphorylation of JNK and p38 mitogen-activated protein kinase (37). The IRE1-dependent JNK activation is an important signaling mechanism that activates the transcription factor CHOP and NF-κB, which causes changes in gene expression that favor apoptosis and inflammatory responses (51). In addition, IRE1 is also implicated in the activation of autophagy (10). The TRAF2-dependent activation of IRE1 and JNK reportedly results in the phosphorylation of Bcl-2, allowing the dissociation of Beclin-1, activation of the phosphatidylinositol 3-kinase complex, and autophagy (52,53). A study by Hetz et al. (54) reported that proapoptotic proteins Bax and Bak activate the IRE1α signaling in the ER and established the association between apoptosis and UPR. Similarly, another study by Klee et al. (55) suggested that the enforced expression of the proapoptotic BH3-only proteins in the ER initiates the activation of the JNK pathway in an IRE1α- and Bak-dependent manner. In contrast, the cytosolic chaperone heat shock protein 72 (Hsp72) was recently shown to reduce the cell damage under ER stress conditions (56). These results provide for the first time an interconnection between cytosolic chaperones and the UPR. Beyond its role in the maintenance of secretory cells and lipid metabolism, the IRE1/XBP1 axis was shown to regulate immune responses. The XBP1 is important for the development and survival of dendritic cells and in the immune response to challenge by pathogens that activate the Toll-like receptors (TLRs) (57,58). Qiu et al. (59) demonstrated that IRE1α is required for production of proinflammatory cytokines, as evidenced by impaired TLR-induced cytokine production in IRE1α-null macrophages and neutrophils, suggesting that IRE1α is a potential therapeutic target for autoimmune disease. Recently, Lerner et al. (60) demonstrated that IRE1 induces thioredoxin-interacting protein, which subsequently activates the inflammasome complex–mediated cell death, suggesting that the ER stress and thioredoxin-interacting protein axis could be a target for effective treatment. Taken together, the IRE1/XBP1 axis is the key in maintaining the various physiological processes and plays a bifunctional role in cell death and adaptation to stress, depending on cell types and extent of the stress stimuli.

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PERK pathway

Double-stranded RNA-dependent protein kinase–like ER kinase is a type I transmembrane protein located in the ER that senses the accumulation of misfolded or unfolded proteins in the ER (42). Like IRE1, the ER domain of PERK senses unfolded proteins, whereas the cytoplasmic domain possesses kinase activity. In the absence of ER stress, GRP78 binds to the ER domain of PERK and inhibits its activation. Under ER stress conditions, PERK separates from GRP78 and is activated through oligomerization and transphosphorylation. Activation of PERK inhibits general protein translation into the ER through the inactivation of the initiation factor eIF2α by serine 51 phosphorylation. This phosphorylation suppresses the guanine nucleotide exchange factor eIF2β, a complex that recycles eIF2α to its active GTP-bound form. This inhibitory effect of translation helps to reduce the ER stress by decreasing the further influx of misfolded or unfolded proteins into the ER.

Furthermore, the phosphorylation of PERK is regulated through the feedback mechanism by specific phosphatases, such as a constitutive repressor of eIF2α phosphorylation (CReP) and its regulatory subunit GADD34 (growth arrest and DNA damage–inducible protein-34) (61). In contrast to global translational attenuation, phosphorylation of eIF2α enhances the translation of activating transcription factor 4 (ATF4). The ATF4 is a transcription factor that induces another transcription factor CHOP, which is involved in the induction of apoptosis that upregulates a pool of UPR genes that function preferentially in amino acid import, glutathione biosynthesis, and combating oxidative stress (35,62). Interestingly, a study by Cullinan et al. (63) identified the nuclear factor (erythroid-derived 2)–like 2, a transcription factor that controls the regulation of oxidative stress as a novel PERK substrate. It has also been demonstrated that PERK may also control the expression of NF-κB in an ATF4-independent manner (64).

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ATF6 pathway

The ATF6 is a type II ER transmembrane protein located in the ER. There are two genes for ATF6, called ATF6α and ATF6β, which have a similar function and are ubiquitously expressed (65). Similar to IRE1 and PERK, the ER domain of ATF6 is responsible for the sensing of unfolded or misfolded proteins; however, the cytoplasmic portion has a DNA-binding domain containing the basic-leucine zipper motif and a transcriptional activation domain (66). In normal conditions, the ATF6 is synthesized as an inactive precursor and binds to the GRP78. As such, the binding association with GRP78 impedes the Golgi localization signal and inhibits the translocation to the Golgi apparatus (15).

Under ER stress conditions, ATF6 is separated from GRP78 and translocates to the Golgi apparatus by vesicular transport. In the Golgi apparatus, it is cleaved by a pair of processing proteases, called site 1 protease and site 2 protease (S2P). This proteolysis results in the release of its cytoplasmic domain, ATF6f (a fragment of ATF6), an active form of ATF6. The active fragment of ATF6 translocates into the nucleus and enhances molecular chaperones and several genes associated with ERAD and protein folding, such as GRP78, GRP94, and calreticulin, as well as the ER stress response element (67–69). Interestingly, recently, several other putative ATF6 homologs have been identified, which are modulated by ER stress in specific tissues, including CREBH, OASIS, CREB4, LUMAN/CREB3, and BBF2H7 (70–72). The cleavage of ATF6 is conserved and different, especially as the second cleavage by S2P occurs in the ER transmembrane. This process is called regulated intramembrane proteolysis, which is well conserved from bacteria to mammals. The known substrate of regulated intramembrane proteolysis is sterol response element–binding protein (SREBP), a transcription factor (73). Similar to ATF6, SREBP is also located in the ER membrane. In the condition of sterol deficiency, SREBP is transported to the Golgi apparatus, cleaved by site 1 protease and S2P, and activates the transcription of genes associated with biosynthesis of sterol (18).

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UPR-independent ER stress

A key signal transduction pathway connecting apoptosis to ER-mitochondrial interactions is an alteration in intracellular calcium (Ca2+) homeostatic mechanisms. The ER is the major site for Ca2+ storage. In the ER, Ca2+-binding chaperones mediate the proper folding of proteins and regulates a diversity of cellular responses and signaling transduction pathways. The Ca2+ transfer between the ER and mitochondria represents a critical signal in the induction of apoptosis. Several studies demonstrated that acute release of Ca2+ from the ER can trigger a variety of signaling mechanisms that promote cell death mainly by Ca2+-mediated mitochondrial cell death (74,75). There are increasing reports that Bax and Bak are involved in Ca2+-mediated apoptosis in the ER (76,77). Overexpression of Bax results in the release of ER Ca2+, with a subsequent increase in mitochondrial Ca2+ that leads to the release of cytochrome c from the mitochondria to the cytoplasm. A family of Bcl-2 proteins such as Bcl-2 and Bcl-xL also located in the ER membrane and are reported to be protective against ER stress (8). It is believed that this cytoprotective function is mainly caused by the ability of Bcl-2 to lower steady-state levels of ER Ca2+. The protective effect of Bcl-2 in the regulation of ER Ca2+ is inhibited by phosphorylation of the JNK pathway (78). Phosphorylated Bcl-2 loses its antiapoptotic function and increases Ca2+ release from the ER, which is associated with mitochondrial Ca2+ uptake and apoptosis (74).

Calreticulin, a major Ca2+-binding ER chaperone, plays an important role in the adequate folding of newly synthesized proteins (79). Therefore, fluctuations or alterations in the Ca2+ level in the ER might impact folding capacity and initiate the components of cell death. A study by Lim et al. (80) reported that enhanced calreticulin expression in mature cardiomyocytes disrupts intracellular calcium regulation, leading to calcium-dependent apoptosis. Thus, alterations in Ca2+ dynamics seem to play a key role in the ER stress–associated mechanisms of cell death.

Recently, a new signaling pathway associated with ER stress has been identified where Cdk5 and MEKK1 induce apoptosis in a Drosophila model of retinitis pigmentosa, independently of the three traditional UPR branches, IRE1α, PERK, and ATF6 (81). In this study, Kang et al. (81) have shown that Cdk5 phosphorylates MEKK1 (human ortholog; MAP3K4) and activates the JNK signaling pathway for apoptosis followed by ER stress. Ablation of this pathway delayed age-associated retinal degeneration in the Drosophila model of retinitis pigmentosa. Recently, Giorgi et al. (82) revealed that p53 activation increases the mitochondrial Ca2+ loads and subsequently enhanced the apoptosis in a Ca2+-dependent manner. Interestingly, they found that pharmacological inhibition of p53 or naturally occurring p53 missense mutants inhibits Ca2+ signaling from ER to the mitochondria. These findings define a novel function of p53 in regulating Ca2+-dependent apoptosis. Murine caspase-12 is a member of the caspase family and has been reported to play an important role in ER stress–mediated cell death (38,83). Murine caspase-12 shows similar characteristics to the human caspase-4, which is located within caspase-1/ICE genes (83). A study by Morishima et al. (84) have suggested that caspase-12 activation is not dependent on mitochondrial or any death receptor activation, and its activation triggers the ER-specific caspase cascade that leads to apoptotic death. This theory was further supported by another finding by Rao et al. (85) where they found that inhibition of caspase-12 reduced the thapsigargin-induced cell death, suggesting an important role of caspase-12 in ER stress–mediated cell death.

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ER stress in sepsis

Improving the quality of life and reducing mortality from sepsis remain two of the most significant unmet medical needs of the current era. New researches on ER stress signaling have recently revealed a new and fascinating interaction between ER stress and sepsis-associated cell death (29,31,32,86). Recently, a number of investigators have reported that the suppression of ER stress stabilizes protein conformation, facilitates the trafficking of mutant proteins, and improves ER folding capacity and suggested that ER stress is a potential therapeutic target for various diseases including diabetes, cystic fibrosis, sepsis, trauma and hemorrhage, and ischemic injuries of brain, kidney, spinal cord, and liver (87–90). This has been demonstrated in CLP models of sepsis, where ER stress contributes to abnormal lymphocyte apoptosis during sepsis in mice, suggesting that the ER stress–mediated apoptotic pathway may be a novel target in clinical prevention and therapy of sepsis-induced lymphocyte apoptosis (29,91). Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis, and myocardial apoptosis is a key step for this progression. A very recent study reported that components of ER stress (GRP94, CHOP, and caspase-12) were upregulated in the hearts of septic rats, and inhibition of ER stress protected the myocardium from ER stress–induced apoptosis in rats (24). The CHOP/GADD153 (growth arrest/DNA damage) plays a convergent role in the UPR and has been identified as one of the most important mediators of ER stress–induced apoptosis (33,35,36,92). There are several targets of the CHOP including GADD34; DR5 (TRAIL receptor-2), a caspase-activating cell surface death receptor of the TNF receptor family; and Ero1α (endoplasmic reticulum oxidoreductase 1), which hyperoxidizes the ER and promotes apoptotic cell death (8). A study by Li et al. (93) has reported that Ero1α activates the inositol triphosphate receptor–induced excessive Ca2+ transport from the ER to the mitochondria, and initiate the apoptosis in macrophages. This finding sheds new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an Ero1α–inositol triphosphate receptor pathway and small-interfering RNA of Ero1α suppresses apoptosis (93). The significance of ER stress in apoptosis was reported in CHOP-deficient mice where in the embryonic fibroblasts revealed that CHOP deficiency provides partial resistance to ER stress–induced apoptosis (94). A study by Gupta et al. (56) have stated that Hsp72 protects rat pheochromocytoma PC12 cells from ER stress–induced apoptosis via enhancement of IRE1α-XBP1 signaling, suggesting an important and critical role of ER stress. Discrepancies in the finding on the role of ER stress from prodeath to prosurvival warrant further deep understanding, which could help develop a therapeutic intervention.

During sepsis, uncontrolled inflammation and activation of the innate immune system may contribute to tissue damage and ultimately cell death. Transcription factor CHOP is a major inducer of apoptosis in response to ER stress; however, recent evidence suggested an inflammatory role of CHOP as a mediator of the inflammatory response in sepsis. Recently, Ferlito et al. (32) reported that septic mice exhibited increased expression of CHOP, and treatment with H2S increased the survival rate in an experimental model of sepsis by inhibiting the CHOP expression, suggesting the participation of ER stress in sepsis. They have highlighted a major role for CHOP, which acts as an amplifier of the inflammatory response in the pathogenesis of sepsis and the ability of H2S treatment to counter CHOP signaling via upregulation of nuclear factor (erythroid-derived 2)–like 2 (32). Moreover, the ER stress pathway involving CHOP is activated in immunostimulated macrophages, suggesting an important role for this response in the pathogenesis of lipopolysaccharide-induced inflammation. This pathway is also activated in the lungs of lipopolysaccharide (LPS)-treated mice, where damage could be inhibited in CHOP-knockout mice (95). These findings further demonstrate that the CHOP-mediated ER stress plays an essential role in the pathogenesis of septic injury in mice. Moreover, Kim et al. (14) have reported that LPS injection in mice induces ER stress and upregulates the UPR-related markers including ATF6, XBP1, phospho-eIF2α, and ATF4, along with Bip and CHOP and recognized the possibility that inhibition of ER stress using a specific ER stress inhibitor 4-phenylbutyrate (4-PBA) attenuates LPS-induced lung inflammation in mice. This study has provided a new concept in the pathogenesis of LPS-induced lung inflammation, which is associated with ER stress that may be one of the promising therapeutic targets for LPS-related diseases.

Signaling pathways in response to ER stress that lead to inflammation and apoptosis are intertwined through a variety of mechanisms, including Ca2+ influx, ROS generation, caspase activation, and phosphorylation of NF-κB. A study by Toltl et al. (34) has reported that inhibition of ER stress by activated protein C suppressed the inflammation and apoptosis in human blood monocytes, and this may partly explain the protective effects of activated protein C treatment in severe sepsis. Recently, caspase-12 was reported to negatively regulate the inflammasome activation by recruiting caspase-1 and impeding the complex formation (96). Interestingly, they also reported that caspase-12–deficient mice were shown to be resistant to septic shock in an experimental mouse model of sepsis, suggesting the critical role of caspase-12 in sepsis conditions. Fernandez and Lamkanfi suggested that caspase-12 directly binds to the microbial components and hampers the replication of pathogens by inducing pyroptosis and confers resistance against sepsis (97). Moreover, the association of human caspase-12 with susceptibility to sepsis in individuals of African and Indian populations has been documented by previously published studies (30,98). Saleh et al. (96) demonstrated that caspase-12 deficiency confers protection in septic mice, and the presence of caspase-12 leads to enhanced vulnerability to bacterial infection and septic mortality, suggesting a detrimental role of caspase-12 in sepsis.

Inhibitions of ER stress by treatment with chemical chaperones, such as 4-PBA or tauroursodeoxycholic acid, suppresses LPS-induced inflammatory and apoptotic expressions in mice and normal human bronchial epithelial cells, suggesting a role of ER stress in sepsis-associated cell death (14). A very recent study by Diao et al. (99) reported that burn plus LPS promotes the inflammasome and ER stress in rat liver, as evidenced by an increased level of CHOP and sXBP1. These observations increase our knowledge of the biological mechanisms in the context of ER stress and sepsis and simultaneously shed light on new targets and suggest novel strategies for the treatment of this condition. Further research is warranted to elucidate the exact mechanism how ER stress contributes to the sepsis-associated cell death.

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ER stress after trauma and hemorrhage

Traumatic hemorrhagic is a pathological condition resulting from traumatic insult and characterized by rapid and significant blood loss. The trauma-hemorrhage–induced immunosuppression is associated with an increased susceptibility to sepsis, organ dysfunction, and ultimately death (9,100). There is growing evidence that ER stress initiates the deleterious cascade and eventually contributes to organ dysfunction after trauma and hemorrhage (9,89,101,102). Increased oxidative stress, hypoxia, and proinflammatory cytokines, hallmarks of the post–trauma-hemorrhage condition, can initiate ER stress (17). Moreover, altered adenosine triphosphate and glucose levels disturb the complex ER machinery as well as the posttranslational modification of newly synthesized proteins or lipids (103). These deleterious events alter the redox environment of the cell and are supposed to interfere with the protein-folding machinery of the ER, leading to the accumulation of unfolded or misfolded proteins inside the ER.

A study by Duvigneau et al. (102) recognized the possibility of contribution of ER stress–associated cell death in rats after trauma-hemorrhage. Jian et al. (9) have demonstrated the role of ER stress and subsequent activation of the UPR and the elevated apoptosis in a murine model of trauma and hemorrhage. Sodhi et al. (104) investigated the involvement of ER stress in trauma/hemorrhage-induced lung injury. In this study, they reported that activation of epithelial TLR4 and high-mobility group box 1 enhances lung injury, and inhibition of TLR4 signaling by TLR4 inhibitors reduced the ER stress, decreased the high-mobility group box 1, and protected against lung injury. Similarly, Kozlov et al. (101) demonstrated that ER stress contributes to the pathogenesis of trauma and hemorrhagic shock in rats, suggesting an important and deleterious role of ER in the propagation of components of cell death. Moreover, sustained ER stress and ROS expedite Ca2+ release of ER, which can activate both mitochondria-dependent and mitochondria-independent caspase cascades, ultimately leading to apoptosis or necrosis (102,105). A recent study by Begum et al. (89) reported that sustained ER stress plays a key role in the progression of neuronal damage in a rat model of traumatic brain injury and suggested that inhibition of ER stress reduces abnormal protein accumulation and neurological deficits. Moreover, He et al. (106) suggested that inhibition of CHOP after hemorrhage in rats reduces apoptosis and vascular injury, suggesting the role of the ER stress component in hemorrhage-induced cell death.

Blast-induced trauma causes blood-brain barrier damage and induces inflammatory cascades that promote intracellular Ca2+ accumulation (107,108). The Ca2+ perturbations are known to cause ER stress and trigger the UPR. Blast-induced ER stress mediated CHOP elevation, along with increased caspase-12 and caspase-3 cleavage, suggesting a neuronal shift from the repair response to apoptosis in rats (108). Moreover, modulation of the ER stress response with ER stress modulator salubrinal has been shown to attenuate PERK-dependent CHOP expression and limit apoptosis, suggesting that suppression of ER stress could be an effective therapy related to trauma and hemorrhage. Recently, Yu et al. (109) demonstrated that prolonged stress induced ATF6-dependent ER stress and its components in the rat brain, indicating the participation of ER stress in posttrauma-induced apoptosis. Further studies are needed to dissect the possible mechanisms how ER stress contributes to trauma-hemorrhage–induced cell death and to develop new therapeutic approaches for the prevention and treatment of trauma-hemorrhage.

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ER stress after I/R injury

Endoplasmic reticulum stress plays an important and essential step in the progression of I/R injury in rodents and humans (110–115). Ischemia/reperfusion injury affects the integrity of the ER, the site of synthesis and folding of numerous proteins. After I/R injury, the ER recognizes any perturbations caused by increased oxidative stress, alteration in calcium homeostasis, accumulation of unfolded proteins, and hypoxia and leads to the activation of the UPR signaling pathway (Fig. 3). A study by Miyazaki et al. (111) reported that the ER stress–induced CHOP-mediated pathway has a deleterious effect on the development of myocardial I/R injury and deficiency of CHOP attenuated the myocardial apoptosis in mouse myocardial I/R injury. Terai et al. (116) presented the evidence that the UPR is activated in neonatal rat cardiomyocytes in response to hypoxia and may play a role in the pathogenesis of heart disease. Tao et al. (110) demonstrated that apelin, an endogenous ligand for the G protein–coupled APJ receptor, protects the heart in a rat model of I/R injury via modulation of ER stress–mediated apoptosis in a time-dependent fashion, suggesting a deleterious role of ER stress in cardiac I/R injury. Several studies have investigated and reported that inhibition of ER stress provides protection against organ I/R injury. A recent study by Mizukami et al. (88) suggested that inhibition of ER stress by chemical chaperone 4-PBA reduces the loads of unfolded proteins in the ER and protects the cell from spinal cord ischemia in rabbits. Dong et al. (90) described the deleterious role of CHOP in apoptosis after mouse renal I/R injury and suggested that targeting CHOP expression may be promising in the treatment of renal I/R. A study by Sun et al. (117) suggested that N-acetyl cysteine treatment provides protection against mouse liver I/R injury and reduces the ER stress in mouse hepatocytes. Vilatoba et al. (118) suggested that chemical chaperone 4-PBA reduced the loads of unfolded protein in the ER and ameliorated the apoptosis via inhibition of CHOP, caspase 12, and peIF2α in rodent models of liver I/R injury. Recently, Rao et al. (27) reported that alleviation of ER stress by chemical chaperone 4-PBA or ATF6 small-interfering RNA diminished the proinflammatory response in mouse Kupffer cells, leading to the inhibition of liver immune response and protection of livers from I/R injury. In contrast, upregulation of ER chaperones protected mouse cardiomyocytes from ER stress–induced apoptosis (119). These findings suggest that the ER stress response is essential for the homeostasis of cardiomyocytes. All the above findings in the context of ER stress and I/R injury presented the evidences that ER stress participates and contributes in I/R injury–associated cell death. Thus, targeting the ER-associated cell death pathway might offer a novel approach to reduce I/R injury. Further studies and better understanding of the reciprocal interaction of ER stress and I/R injury are essential to shed new insights into the possible mechanisms and new therapeutic approaches for the prevention of I/R injury.



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Perspectives and future directions

The ER plays a critical and dynamic role in cellular physiology by ensuring the correct folding of secretory and transmembrane proteins. However, the precise molecular mechanisms by which ER stress leads to cell survival/death remain enigmatic. During the past decades, new research has provided exciting evidences that activation of the UPR not only maintains a homeostatic environment in the ER but also is involved in the regulation of a wide variety of other cellular processes, including cellular proliferation and differentiation, inflammation, apoptosis, and angiogenesis. Moreover, as documented by several investigators, activation of the UPR seems to be a dynamic process closely correlated with the duration and severity of ER stress. Accordingly, increased ER stress and UPR activation have been reported in many human diseases, including cancer, ischemia, neurodegenerative diseases, diabetes, and metabolic disorders. In this review, we highlighted that, during normal conditions, concerted action of ER stress components is required to maintain cellular homeostasis after sepsis, trauma, and I/R injury. Imbalance in these regulatory components, which could lead to apoptosis (Fig. 3), as often seen in several pathological conditions, presents a challenge to develop therapies to restore such homeostasis.

From a therapeutic perspective, it will be of great importance to understand how the UPR could be pharmacologically manipulated to switch from prodeath to prosurvival pathways. In recent years, pharmacological compounds targeting PERK, IRE1, and ATF6 have been used in disease models and are beginning to show promising properties. Understanding the cross talk among the various components of the UPR as well as how these signaling pathways are intertwined with initiation of inflammatory and apoptotic cascade will provide new treatment options for various pathologies including sepsis, trauma, and hypoxia. Moreover, recent findings on caspase-12 activation during sepsis, trauma, and I/R injury open a new field for therapeutic strategies focused on modulation of caspase-12 and shed new light on its physiological role.

In summary, the ER is an external stimulus–sensing device that could sense any alterations in the microenvironment of the cells from toxins to pathogens. It could serve as a rich platform for understanding the interactions between environmental signals and the biological response. Hence, investigation of ER stress and its associated UPR signaling represents a new and exciting area to explore in the field of sepsis, trauma, and I/R injury.

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ER stress; UPR; sepsis; inflammation; apoptosis; ASK1; apoptosis signal-regulating kinase 1; ATF4; activating transcription factor 4; ATF6; activating transcription factor 6; Bip; binding immunoglobulin protein; CHOP; C/EBP homologous protein; eIF2; eukaryotic initiation factor 2; ER; endoplasmic reticulum; ERAD; ER-associated degradation; Ero1α; endoplasmic reticulum oxidoreductase 1; I/R; ischemia/reperfusion; GRP78; glucose-regulated protein; IRE1; inositol-requiring protein 1; JNK; c-Jun N-terminal protein kinases; PERK; double-stranded RNA-dependent protein kinase–like ER kinase; 4-PBA; 4-phenylbutyrate; ROS; reactive oxygen species; TRAF2; TNF receptor–associated factor 2; UPR; unfolded protein response; XBP1; X-box–binding protein 1

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