Besides modulating cancer cell function intrinsically, IRE1 profoundly regulates immune cells in the TME, which will be discussed later. Apart from inflammatory regulation, IRE1 pathway has also been implicated in metabolic diseases including obesity and diabetes Using several well-established mouse obesity models such as high fat diet HFD induced obese mouse model and leptin deficient mouse model, it was found that obesity is associated with increased expression of phosphorylated IRE1, PERK, and JNK in adipose tissue and the liver.
Activation of PERK is initiated by dissociation of BiP from its luminal domain resulting in its oligomerization and autophosphorylation This rapid response serves as prosurvival mechanism Remarkably, under these circumstances, some transcripts such as activating transcription factor 4 ATF4 are translated more efficiently. The roles of CNPY2 in inflammation and immune responses are under active investigation. PERK pathway has been implicated in various diseases especially in neurodegenerative diseases and metabolic diseases.
ER stress delays degradation of tau protein and causes hyperphosphorylation of tau, which in turn further amplify UPR, creating a vicious cycle PERK plays important role in regulating immune cells, which will be the subject of later discussion.
ATF6 has been shown to have an essential role in development, as ATF6 null mice are embryonically lethal. Thereafter, free ATF6 translocates from the ER to the Golgi where it undergoes cleavage mediated by two different proteases. The mechanisms regulating ATF6 translocation from the ER to the Golgi, either alone or via interaction with a shuttle protein, remains unclear Figure 1. High ATF6 expression correlates with poor prognosis of colorectal cancer patients which is consistent with the work in the mouse model.
Mouse model with the epithelial-cell-specific overexpression of activated ATF6 spontaneously developed colon adenomas Similar to other ER stress factors, ATF6 null mice are prone to develop hyperlipidemia and insulin resistance ATF6 knockout mouse also exhibit liver dysfunctions and steatosis The ER stress plays critical roles in controlling various intracellular physiological functions including protein folding, calcium homeostasis, lipid metabolism, cell differentiation, and protein translocation Thus, malfunction of the ER stress response has been linked, not surprisingly, to dysregulation of the innate and adaptive immune response.
Recent work has demonstrated that the UPR sensors are involved in regulating the development, differentiation, activation, cytokine production, and apoptosis of multiple immune cell types including T cells, B cells, DCs, macrophages, and MDSCs Figures 2 , 3. As such, the emerging roles of UPR effectors in the immune compartment raise a possibility of targeting UPRs in the management of a number of immune disorders including cancer.
For ease of information flow, we will discuss the roles of UPR in each individual immune cell types, although the impact of UPR on the overall immune response at organismal level is obviously mediated at the multiple cell level. Figure 2. ER stress can modulate the biology of various subsets of immune cells such as cell apoptosis, cytokine production, cell differentiation, antibody production, mitochondrial function, and Toll-like receptor TLR signaling. Figure 3. Endoplasmic reticulum ER stress plays multifaceted roles in inflammation.
ER stress establishes the homeostatic environment of both pro- and anti-inflammation through regulating major immune cells.
In addition, Cao et al. GRP78 BiP also plays an important role in regulating inflammatory cytokine productions in the Crohn's disease-like ileitis.
Table 1. Role of unfolded protein response UPR effectors in specific immune cell populations. XBP1s activity promotes Th17 differentiation and has a critical function in promoting experimental autoimmune encephalomyelitis EAE in mice.
ER stress induces Treg plasticity as well. The canonical stressor, thapsigargin Tg , enhances Il10 transcription in vitro. Gp96 also known as GRP94 , an ER molecular chaperone, is upregulated by ER stress and plays multiple roles in immunological activities The physiological importance of UPR in B-cell differentiation and function has been demonstrated by multiple studies. The UPR effectors are elevated in B cells during differentiation into plasma cells and are required for efficient antibody production 24 , 25 , — XBP1-deficient B cells can develop and be activated normally, but they failed to produce immunoglobulins 24 , These findings indicate that XBP1 and its downstream molecules regulate B-cell differentiation and immunoglobulin production.
B-lymphocyte-induced maturation protein-1, which transcriptionally regulates ATF6 and ER to nucleus signaling 1 Ern1 , encoding IRE1, was found to play important role in regulation of plasma cell differentiation and antibody production as well In addition, ER stress regulates production of proinflammatory cytokine by activating B cells.
Induction of ER stress by Tg treatment upregulates proinflammatory cytokine gene expressions e. These observations indicate the potential role of ER stress in B-cell differentiation and function in normal conditions and in diseases Table 1. DCs, which serve as professional antigen-presenting cells, are critical for the initiation of an adaptive immune response, and DCs are tightly regulated by ER stress , XBP1-deficient lymphoid chimeras possess decreased numbers of both conventional and plasmacytoid DCs in mice, a phenotype that could be rescued by XBP1s overexpression in the hematopoietic progenitors.
XBP1s can also promote IL production via mitochondrial ROS, in situations when excess fatty acid accumulates in the immediate milieu, resulting in impaired glycolysis This study also showed that XBP1s elevate the triglyceride biosynthetic program in tDCs, which led to the abnormal lipid accumulation and diminished antigen presentation.
In the allogeneic bone marrow transplant setting, the inhibition of XBP1s reduced targeted organ damage and pathogenic Th1 and Th17 development without impacting donor Tregs or antitumor CTL.
These findings were explained as a result of impaired generation of monocyte-derived DCs, leading to decreased alloactivation of T cells DCs also play an important role in brain immunity.
DCs are located in choroid plexus, pia mater, and dura mater, but not in the perivascular space of brain. These suggest that DCs may play a major role in recruiting T cells into the brain area. These contrasting observations draw attention to the potential pitfalls in connecting ER stress in DCs to diseases Table 1. Macrophage is a crucial cell type involved in innate immunity which largely functions through phagocytosing pathogens and producing inflammatory cytokines.
The polarization of macrophages is important for their function in producing pro- or anti-inflammatory cytokines Despite regulating obesity and the cystic fibrosis, the roles of macrophage in liver diseases are closely linked to ER stress. Overall, targeting ER stress as a means to repolarize M2 macrophages in the TME may be an enticing therapeutic approach. Natural killer NK cells are critical controller of host immunological homeostasis and pathogenesis.
Our group have shown that platelet is a crucial mediator in antitumor immunity The formation of platelets is mediated by ER stress. Using ER stressor, caspase-4 was inhibited in the megakaryocytes, which enhanced platelets production However, the detailed mechanism is still not clear. Given the role of prolonged ER stress in multiple chronic medical conditions, considerable efforts have been made to develop small molecules that can reduce ER stress. However, most of the agents have not been tested for their immunological properties particularly in relevant clinical models in vivo.
Here, we summarize the mechanisms and current use of these UPR component inhibitors Table 2 , Figure 4 and call for future investigation of their use in immune modulations. Figure 4. Pharmacological strategies to control endoplasmic reticulum ER stress in diseases.
STF, a compound selectively inhibiting ER stress-initiated endonuclease activity of IRE1, also prevents further downstream signaling. Melatonin has also been reported to selectively inhibit ATF6. MKC induces modest growth inhibition without toxic effect in normal cells; however, in combination with conventionally used drugs, MKC significantly induces cancer cell death MKC also shows cytotoxicity against acute myeloid leukemia by inducing cell cycle arrest STF shows inhibitory effects in multiple myeloma xenografts mouse model.
STF shows preferential cytotoxic effect to freshly isolated multiple myeloma cells when compared to other isolated immune cell populations such as B cells or NK cells In liver, STF treatment alleviates carbon-tetrachloride-induced liver damage and fibrosis Toyocamycin also markedly inhibits ER stress in multiple myeloma cells, resulting in potent cytotoxic effect GSK treatment can inhibit M1-type macrophage polarization induced by ER stress and also increase glucose-stimulated insulin secretion 86 , Despite promising therapeutic effects, off-target issues have been reported for both inhibitors.
Moreover, downstream pathway molecules are also the potential targets for ER stress. Development of an ATF6 inhibitor has been challenging, thanks in large part to the lack of druggable binding sites as well as minimal information in regards to its protein structure However, using cell-based high-throughput assay, Ceapins were identified as potent ATF6 inhibitor Melatonin has also been identified as novel selective ATF6 inhibitor.
Melatonin selectively blocks ATF6 and further reduce cyclooxygenease 2 expression. This inhibition resulted in enhanced liver cancer cell death under ER stress Based on therapeutic effects of Ceapins in ER-stress-related diseases, further optimization of Ceapins is required. UPR is an essential checkpoint for the ER homeostasis and serves as a physiological sensor for the stress from the accumulation of misfolded proteins in the ER. Over the decades, role of ER stress in diseases has been broadly revealed including obesity, autoimmune diseases, cancer, liver diseases, neurodegenerative diseases, and others.
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The endoplasmic reticulum ER is an important subcellular organelle involved in the synthesis, post-translational modifications, and proper folding of secretory proteins, and calcium homeostasis 4. A variety of physiological conditions, including hypoxia, stress, hypoglycemia, calcium depletion, oxidative stress, and a high-fat diet, can disrupt the protein folding process and consequently result in the accumulation of unfolded and misfolded proteins in the ER, a condition termed ER stress 5.
Under ER stress, the unfolded protein response UPR is activated to minimize the overloading caused by the unfolded proteins. However, if ER functions are severely damaged, apoptosis signals are triggered 6. Many cellular processes require ER chaperone involvement, including the transfer of newly synthesized peptides on the ER membrane, the folding and assembly of proteins, the degradation of misfolded proteins by the ubiquitin-proteasome system, the autophagy-lysosomal system, and the regulation of calcium homeostasis, which act as stress sensors for the ER 8 — Multiple studies have demonstrated that ER stress is associated with psychiatric disorders.
Bown et al 12 revealed that levels of the ER stress proteins GRP78, GRP94 and calreticulin are elevated in the postmortem temporal cortex of patients with major depressive disorder MDD , with Nevell et al 13 similarly demonstrating that systemic and persistent activation of ER stress is associated with MDD. Another study reported that stressful life events across the lifespan play an important role in disease etiology Stress is one of the common causes of depressive episodes; sustained stress can also disrupt hippocampal nerve regeneration in adults, indirectly inhibit dopamine function, and exaggerate the amygdala's memory of negative stimuli Therefore, it is hypothesized that ER stress may be a major culprit in the progression of depression.
This review aimed to summarize the current knowledge of the role of ER stress in depression. ER stress refers to the molecular and biochemical changes in the homeostatic morphology and function of the ER upon the stimulation of cells by internal or external factors, which block the processing and transport of proteins, and lead to the accumulation of large amounts of unfolded or misfolded proteins in the ER As a result, cells take corresponding measures to relieve ER stress and promote the recovery of normal ER function.
Cellular survival is only achieved when the ER stress response resolves these stimuli and produces normal proteins If residual unfolded proteins are released as mutants, specific apoptotic responses occur To relieve ER stress and restore homeostatic functions within the ER on a cellular level, the UPR triggers three types of protective cellular responses depending on the cause of induction: The upregulation of genes encoding ER chaperones, the attenuation of translation, or the promotion of ER-associated degradation ERAD of aggregated proteins These are adaptive responses to protein accumulation in the ER and relieve ER stress by reducing protein synthesis, promoting protein degradation, and increasing molecular chaperones that help protein folding.
In unstressed cells, these ER transmembrane signaling molecules are maintained in an inactive state by binding to GRP78 A variety of physiological conditions can disrupt the protein folding process and consequently result in the accumulation of unfolded and misfolded proteins in the ER, a condition termed ER stress. If the UPR is successful in reducing the number of unfolded and misfolded proteins, UPR signaling is attenuated and the cell survives. In addition, ATF4 serves a protective role by regulating amino acid metabolism, redox reactions and protein secretion Collectively, these transduction pathways coordinate together to counteract ER stress through negative feedback, reducing the number of unfolded proteins and facilitating cell survival Nonetheless, when the mechanism fails, a large amount of calcium is released into the cytoplasm to induce apoptosis, whilst persistent UPR signals induce chronic ER stress When the function of ER is severely impaired, a large amount of calcium is released into the cytoplasm to induce apoptosis.
Rats or mice exposed to chronic unpredictable mild stress CUMS are widely used as depression models Previous results have suggested that the depressive behavior of CUMS mice is related to ER stress, and that the underlying mechanism is the insufficient synthesis of ATP, and the overactivated oxidative and ER stress which leads to neuronal apoptosis or death Another previous study reported that CUMS-induced depression-like behavior in rats is due to the disturbance of hippocampal hydrogen sulfide H 2 S generation, which in turn promotes hippocampal ER stress responses including the upregulation of GRP78, CHOP, and cleaved caspase expression H 2 S is the third most prevalent endogenous signaling gasotransmitter and serves a key role in both neuromodulation and neuroprotection Moreover, H 2 S has been suggested to inhibit hippocampal ER stress by upregulating hippocampal silence signal regulator 1, an essential metabolically regulated transcription factor, thereby attenuating depression-like behaviors in rats These findings suggest that H 2 S may provide a novel target for the treatment of depression.
Recent evidence has demonstrated that chronic restraint stress CRS induces cognitive impairment, and anxiety- and depression-like behavior in rodents Previous findings by Jangra et al suggest that honokiol a traditional Chinese medicine isolated from the bark of Magnolia officinalis tree eliminates CRS-induced cognitive impairment and depressive-like behavior by preventing the elevation of GRP78 and CHOP in the hippocampus of mice Furthermore, in CRS mice, the expression levels of GRP78 and CHOP in the hippocampus, and of CHOP in the prefrontal cortex, are significantly upregulated compared with those in the control group, while sodium phenylbutyrate an ER stress inhibitor and edaravone a free radical scavenger not only reverse the high expression of these genes, but also improve the cognitive deficits and depression-like behavior observed in the model mice Lipopolysaccharide is an endotoxin that causes anxiety- and depression-like behavior in rodents after central or peripheral administration Its administration is reported to significantly upregulate GRP78 mRNA expression in the hippocampus, suggesting that UPR is involved in lipopolysaccharide-evoked behavioral anomalies Social defeat stress-vulnerable mice also demonstrate depression-like behavior, which is associated with a significant increase in the expression of GRP78, CHOP and choline acetyltransferase in the amygdala Liu et al found that the expression of GRP78 and XBP1 were significantly increased in the hippocampus of mice with social defeat stress Sharma et al also demonstrated that inhibition of PERK expression in the hippocampus can enhance hippocampal-dependent memory and reverse memory deterioration in mice 47 , suggesting that cognitive function can be improved by regulating the expression levels of PERK at the Cornu Ammon 1 region of the hippocampus.
Spinal cord injury in rodent models causes depressive-like behavior and impairment of spatial memory retention 49 — Experimental studies have reported that chronically activated ER stress in the brain and newly formed immature neurons in the subgranular area of the hippocampus may be detrimental to the survival and regeneration of impaired cognitive and depressive neurons following spinal cord injury In summary, the above animal studies have demonstrated a link between ER stress and depression.
In addition, DDIT3 can activate the formation of autophagosome through downregulation of Bcl-2 expression [ ]. CHOP is another potent transcription factor, which is involved in the induction of autophagy [ , ].
Besides, the Bcl-2 expression level is downregulated, which assists in the release of Beclin-1 from Bcl Beclin-1 phosphorylation leads to decreased Bcl-2 expression and initiates the formation of a complex between the autophagosome initiator Beclin-1 and PIK3C3.
It forms two complexes, the mTORC1 and mTORC2, both of which are triggered by extracellular and intracellular stimuli, under favorable conditions for growth [ , ]. Interaction of growth factors with insulin triggers the PI3K complex, which accelerates the plasma membrane adaptation of the lipid phosphatidylinositolphosphate PtdIns 3 P to generate PtdIns 3,4,5 P2 and PtdIns 3,4,5 P3. The PI3K is elicited as a vesicular protein trafficking mediator, which binds to PtdIns 3 P, resulting in its translocation to intracellular membranes such as endosomal and lysosomal membranes.
PI3K is a member of Vps34 family, which plays an important role in the formation of autophagosomes, by directly interacting with Beclin-1 [ ]. Similarly, PtdIns 3 P and PtdIns 3,4,5 P3 initiate autophagy by phosphorylation of the phosphatidylinositol to activate PtdIns 3,4,5 P3 and contributes to the autophagic vacuole sequestration [ ]. The AMP-activated kinase AMPK is a key cellular energy sensor that regulates the transcription of the autophagy genes through the regulation of many downstream kinases [ ].
In addition, albumin-treated cellular toxicity leads to the activation of AMPK. Inversely, inhibition of IP3Rs can activate autophagy signal that might be mechanically different from ER stress-attenuated autophagy. In hippocampal neuronal stem cells treated of insulin lead to increase expression of RYR3 isoform which instigate cell death through elevate induction of autophagy [ ]. Accordingly, endogenous expression of RYRs in skeletal muscle cells and HEK cells segregates rat hippocampal neurons inhibit the autophagy flux particularly at the autophagosome-lysosome fusion.
Inhibition of calpain by pharmacological calpestatin and calpeptin or knockdown of calpain enhances autophagy flux without turbulence mTORC1 [ ]. Nonetheless, these studies demonstrate that calpain can suppress autophagy induction although other experimental studies suggest that the activation of calpain is essential for autophagy induction [ ].
The UPR pathway is not always a reason for autophagy induction. When ER stress is divergent in some contagious situation, defective regulation of autophagy occurs. Notably, in some pathological conditions such as neurodegenerative, cardiovascular, and liver diseases, ER stress negatively regulates autophagy. Defective regulation of autophagic function leads to AD progression; Pickford et al. Therefore, activation of UPR will not be regulated properly as a result of negative induction of autophagy, which fails to eradicate the accumulation of contagious protein and then consequently leads to neurodegenerative diseases.
UPR and autophagy are also interconnected for inflammation of bowel in the epithelial cell. In addition, XBP1 conditional knock in intestinal epithelial cell lead to induced autophagy in small intestinal paneth cell, essential for the formation of antimicrobial agents followed by inflammation in small intestine, which is more exacerbated when codeletion of ATG gene like ATG7 or ATG16L1.
Moreover, In ATG16L conditional knockout mice enhance GRP78 expression along with phosphorylation of eIF2a and activation of JNK, terminating the expression of IRE1a and increased the XBP1 spicing in intestinal glands, these circumstances increase the inflammation state, which changes the interaction between ER stress and autophagy that increases cell death, which is negative retroaction of ER stress-induced autophagy [ ].
Nevertheless, defective regulation of XBP1 integrates FoxO1 Forkhead box O1 , a transcription factor that sequentially provokes expression of many genes that positively induce autophagy [ 98 ]. Prominently, the consistent mechanism has been proved under severe ER stress in which the UPR loses its activity, whereas it can be considered that another regulatory mechanism FoxO1 maintains the autophagy induction.
During the last decade, research has been conducted to determine the mechanism by which ER stress and autophagy maintain intracellular homeostasis. Here, we described the UPR and autophagy in detail with respect to their molecular mechanism and interaction between ER stress and autophagy. However, the detailed mechanism of ER stress and autophagy is yet to be fully understood. In the last few years, research has shown that the ER stress response can not only initiate autophagy but can also negatively regulate autophagy to maintain cell survival.
Elucidation of the interactions between the UPR and autophagy will help in the development of novel treatments for several diseases.
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