Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

The ocular surface is a gateway that contacts the outside and receives stimulation from the outside. The corneal innate immune system is composed of many types of cells, including epithelial cells, fibroblasts, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, mucin, and lysozyme. Neutrophil infiltration and degranulation occur on the ocular surface. Degranulation, neutrophil extracellular traps formation, called NETosis, and autophagy in neutrophils are involved in the pathogenesis of ocular surface diseases. It is necessary to understand the role of neutrophils on the ocular surface. Furthermore, there is a need for research on therapeutic agents targeting neutrophils and neutrophil extracellular trap formation for ocular surface diseases.

Role of Neutrophils on the Ocular Surface

The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.

/pdf/endoplasmic-reticulum-stress-of-gut-enterocyte-and-16q146lu.pdf

Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases

Fine particulate matter (PM2.5) is a type of small particle that is <2.5 µm in diameter that may cause airway inflammation. Thus, the present study aimed to explore the effects of PM2.5 on endoplasmic reticulum (ER) stress and airway inflammation in human airway epithelial cells. For this purpose, HBE135‑E6E7 airway epithelial cells were cultured and exposed to specific concentrations of PM2.5 for various periods of time, and cell viability was determined using a Cell Counting Kit‑8 assay. The results of the present study demonstrated that exposure to PM2.5 increased the mRNA and protein expression levels of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α and mucin 5AC (MUC5AC). Moreover, the expression levels of ER stress‑related proteins, such as glucose‑regulated protein 78, CCAAT‑enhancer binding protein homologous protein, activating transcription factor 6, protein kinase R‑like ER kinase (PERK), phosphorylated (p‑)PERK, inositol‑requiring enzyme 1α (IRE1α) and p‑IRE1α, and nucleotide‑binding oligomerization domain 1 (NOD1) expression levels were increased following exposure to PM2.5. Transfection with IRE1α small interfering RNA (siRNA) led to the increased production of IL‑6, TNF‑α and MUC5AC. Moreover, the expression of NOD1 and the translocation of NF‑κB p65 were inhibited following transfection with IRE1α siRNA. In addition, the results of the present study demonstrated that transfection with NOD1 siRNA decreased the production of IL‑6, TNF‑α and MUC5AC, and decreased the translocation of NF‑κB p65. The expression levels of IL‑6, TNF‑α and MUC5AC were increased in the HBE135‑E6E7 cells following treatment with C12‑iE‑DAP, a NOD1 agonist. Moreover, treatment with C12‑iE‑DAP led to the activation of NF‑κB p65. Collectively, the results of the present study suggest that PM2.5 promotes airway inflammation and mucin production by activating ER stress in HBE135‑E6E7 airway epithelial cells, and that the IRE1α/NOD1/NF‑κB pathway may be involved in this process. 

pdf/fine-particulate-matter-promotes-airway-inflammation-and-4n2p03fb09.pdf

Fine particulate matter promotes airway inflammation and mucin production by activating endoplasmic reticulum stress and the IRE1α/NOD1/NF‑κB pathway.

Early-life cadmium exposure elevates susceptibility to allergic asthma in ovalbumin-sensitized and challenged mice.

Endoplasmic reticulum (ER) stress is an important reaction of airway epithelial cells in response to various stimuli, and may also be involved in the mucin secretion process. In the present study, the effect of ER stress on neutrophil elastase (NE)‑induced mucin (MUC)5AC production in human airway epithelial cells was explored. 16HBE14o‑airway epithelial cells were cultured and pre‑treated with the reactive oxygen species (ROS) inhibitor, N‑acetylcysteine (NAC), or the ER stress chemical inhibitor, 4‑phenylbutyric acid (4‑PBA), or the cells were transfected with inositol‑requiring kinase 1α (IRE1α) small interfering RNA (siRNA) or X‑box‑binding protein 1 (XBP1) siRNA, respectively, and subsequently incubated with NE. The results obtained revealed that NE increased ROS production in the 16HBE14o‑cells, with marked increases in the levels of ER stress‑associated proteins, such as glucose‑regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R‑like endoplasmic reticulum kinase (pPERK) and phosphorylated (p)IRE1α. The protein and mRNA levels of spliced XBP1 were also increased, and the level of MUC5AC protein was notably increased. The ROS scavenger NAC and ER stress inhibitor 4‑PBA were found to reduce ER stress‑associated protein expression and MUC5AC production and secretion. Further analyses revealed that MUC5AC secretion was also attenuated by IRE1α and XBP1 siRNAs, accompanied by a decreased mRNA expression of spliced XBP1. Taken together, these results demonstrate that NE induces ER stress by promoting ROS production in 16HBE14o‑airway epithelial cells, leading to increases in MUC5AC protein production and secretion via the IRE1α and XBP1 signaling pathways.

/pdf/endoplasmic-reticulum-stress-xbp1-promotes-airway-mucin-4bx0wrp3ex.pdf

Endoplasmic reticulum stress/XBP1 promotes airway mucin secretion under the influence of neutrophil elastase.

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Endoplasmic reticulum stress/XBP1 promotes airway mucin secretion under the influence of neutrophil elastase.