Endoplasmic reticulum stress regulates cell injury in lipopolysaccharide-induced nerve cells

Abstract

Objective Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and excessive endoplasmic reticulum (ER) stress is closely correlated with the cell injury caused by sepsis. This study aimed to analyze the possible role of ER stress in SAE cell models. Methods PC12 and MES23.5 cells were treated with increasing concentrations of lipopolysaccharides (LPS). The Cell Counting Kit-8 assay was used to detect cell viability and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to assess cell apoptosis. In addition, the protein expression levels of ER stress markers [GRP78, CHOP, inositol-requiring enzyme 1 (IRE1), and PKR-like ER kinase (PERK)] and apoptosis-related proteins (Bax, Bcl-2, caspase-3, and cleaved caspase-3) were analyzed using western blotting. Results LPS treatment activated ER stress markers in both the PC12 and MES23.5 cells. The overexpression of GRP78 significantly reduced cell viability and enhanced cell apoptosis in a time-dependent manner. An ER stress inhibitor, 4-PBA, significantly enhanced cell viability and inhibited the cell apoptosis induced by LPS. Therefore, an enhanced unfolded protein response (UPR) and UPR suppression may regulate cell apoptosis. Conclusions UPR was shown to be involved in regulating LPS-induced neuron injury. UPR could be a potential therapeutic target in SAE.

Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4+ T cells against apoptosis and immune dysregulation in sepsis

“…Besides, it is reported that calpain is involved in regulating the activity of Caspase 3 and its upstream molecules Caspase 12 and Caspase 9 34 . ER stress mediates the apoptosis of most cells 7,10,12 . In our study, we demonstrated that LPS and CLP treatments markedly induced ER stress in CD4 + T cells within the appropriate time, as proved by the up‐regulated expression of ER stress markers, including p‐PERK/p‐eIF2α, IRE‐1α, ATF6, ATF4, XBP‐1 s, GRP78, CHOP, p‐JNK, calpain‐1, calpain‐2.…”

“…Activated ER stress markers are responsible for transmitting signals to cell death through different mechanisms. The first is the activation of transcription factor CHOP mediated by PERK, IRE1, and ATF6, which has been reported to promote apoptosis protein Bax and inhibit anti‐apoptosis protein Bcl2 10 . The second is the activation of JNK mediated by the IRE1 pathway, which induces apoptosis by regulating apoptotic proteins such as Bcl2 30 .…”

“…The first is the activation of transcription factor CHOP mediated by PERK, IRE1, and ATF6, which has been reported to promote apoptosis protein Bax and inhibit anti-apoptosis protein Bcl2. 10 The second is the activation of JNK mediated by the IRE1 pathway, which induces apoptosis by regulating apoptotic proteins such as Bcl2. 30 The third is the activation of Caspase-12, which migrates from the ER to the cytoplasm, cleaves Caspase-9 and activates Caspase 3, and participates in cell apoptosis during ER stress.…”

“…ER stress was participated in the pathological mechanism of many diseases, including septic cardiomyopathy, acute lung injury, liver injury, and cardiovascular disease 6–9 . The intense ER stress response leads to cell damage under the pathological conditions of sepsis, such as nerve cells, 10 endothelial cells, 11 cardiomyocytes, 7 lymphocytes, 12 and so forth, which all aggravate the severity of sepsis. However, ER stress is a key factor in the pathology of sepsis 12,13 .…”

Sepsis-Induced Brain Dysfunction: Pathogenesis, Diagnosis, and Treatment

“…In addition to secreting inflammatory cytokines [ 116 ], astrocytes also affect the release of neurotransmitters, which at last leads to neuronal injury [ 117 ]. Sepsis can dysfunction the autophagy and pyroptosis homeostasis [ 118 ] and activate ferroptosis [ 119 ] and endoplasmic reticulum stress of neurons, all of which could lead to neuronal damage [ 120 ]. Abnormal activation of neuronal membrane receptors can transmit stimulus signals and induce PANoptosis [ 121 ].…”