Cadmium induces endoplasmic reticulum stress-mediated apoptosis in pig pancreas via the increase of Th1 cells

Wu, Hao; Zheng, Shufang; Zhang, Jinxi; Xu, Shiwen; Miao, Zhiruo

doi:10.1016/j.tox.2021.152790

Cited by 31 publications

(9 citation statements)

References 48 publications

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“…IRE1 and PERK have a significant association with promoting Th17 polarization 43 . Activation of three branches of ER stress (ATF6, PERK, and IRE‐1) accelerates the development of Th1 cells and the inhibition of Th2 cells 44 . Taken together, these results all confirm our reports that inhibition of ER stress improves T cell dysregulation, which also further indicates the mechanism by which the entire ER stress pathway exerts a destructive effect on CD4 + T cells in early sepsis.…”

Section: Discussionsupporting

confidence: 85%

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

Lü

et al. 2022

IUBMB Life

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Immunosuppression mediated by CD4 + T cell apoptosis and dysfunction is a key factor in promoting the progression of sepsis. Endoplasmic reticulum (ER) stress participates in the apoptosis and dysfunction of immune cells. We aimed to investigate the role of ER stress inhibition in CD4 + T cells in both in vitro and in vivo models of sepsis. In vitro model of sepsis was established with lipopolysaccharide (LPS) and the rat model of sepsis was established using cecal ligation and puncture (CLP). After the LPS treatment or CLP, ER stress inhibitors including 4-PBA, SNJ-1945, and SP600125 were used to treat cells or rats, and the CD4 + T cells were obtained by magnetic bead sorting. The effects of ER stress inhibitors on apoptosis and the function of CD4 + T cells were evaluated. After the LPS stimulation or CLP, the levels of ER stress and downstream markers (PERK, eIF2α, IRE-1α, ATF6, ATF4, XBP-1 s, GRP78, CHOP, and p-JNK) were increased in CD4 + T cells at the beginning of sepsis. Meanwhile, the number of apoptotic CD4 + T cells markedly increased. In addition, sepsis impaired the function of CD4 + T cells, manifested by the increased population of Th1, Th2, Th17, and Treg, as well as the production of TNF-α, interleukin (IL)-6, IL-4, and IL-10. However, inhibitors of ER stress, JNK, and calpain all decreased the induction of Th1 and Th17, enhanced the increase of Th2 and Treg, decreased the production of TNF-α and IL-6, and enhanced the production of IL-4 and IL-10. Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4 + T cell apoptosis and maintaining CD4 + T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis.

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Section: Discussionsupporting

confidence: 85%

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

Lü

et al. 2022

IUBMB Life

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“…The expression of TNF-α is also increased in Cd poisoning rat testis and the expression of IL-4 is also decreased in the same way (Al-Azemi et al 2010). Moreover, the experiments of Wu et al have also shown that TNF-α and IFN-γ expression is increased and IL-4 and CCR4 expression is decreased, causing Th1/Th2 imbalance in Cd poisoning pig pancreas(Wu et al 2021). In this experiment, we detected the Th1 cell markers TNF-α, IFN-γ and Th2 cell markers IL-4 and CCR4 expression levels.…”

mentioning

confidence: 71%

“…Cd poisoning also induces Th1/Th2 cell immune drift. For example, Cd poisoning causes Th1/Th2 balance to shift to Th1 in the pancreas of pigs (Wu et al 2021). IL-6 and interferon-γ (IFN-γ) as Th1 cell markers expression is increased, and IL-10 as Th2 cell markers expression is decreased in Cd poisoning rat testis (Sivaprakasam and Nachiappan 2016).…”

Section: Introductionmentioning

confidence: 99%

Cadmium induced mitochondria apoptosis via the reduction of Th2 cells in pig thyroids

Zhang

Liu

Zhang

et al. 2022

Preprint

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Cadmium, as an environmental pollution element, is considered as a strong toxic substance of organisms. High doses of cadmium have serious cytotoxicity and induces programmed cell necrosis, autophagy, and apoptosis. Th1/Th2 balance is involved in regulating the dynamic balance of cytokine networks and is closely related to the occurrence and development of a variety of diseases. The purpose of this study was to investigate the relationship between Th1/Th2 balance and cadmium-induced apoptosis of thyroid cells. Cadmium poisoning pig model was established in which healthy 6-week-old pigs were exposed to CdCl2 for 40 days (with a dietary cadmium content of 20mg/kg). First, apoptosis was detected by TUNEL staining, and Th1/Th2 equilibrium shift was detected by immunofluorescence. Secondly, the mRNA and protein expression of related proteins were detected by qRT-PCR and Western blot. The results showed that the Th1/Th2 balance shifted towards Th1 and Th2 cells decreased；and the expression levels of Ras/Raf/MEK/ERK pathway related proteins were inhibited in group Cd. In addition, Bax, CytC, Caspase9, and Caspase3 expression increased and Bcl2 expression decreased after cadmium exposure. In brief, our experiments suggested that the pro-apoptosis-related genes expression upregulates and apoptosis induces by activating the mitochondrial pathway signaling pathway in thyroid cells after Cadmium exposure. These negative effects are in connection with the Th1/Th2 imbalance and the reduction of Th2 cytokines.

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“…Wang et al confirmed that Arsenic (As) exposure induces neuronal apoptosis through ER stress‐mediated signaling pathway 34 . Wu et al reported Cd induces apoptosis mediated by ER stress pathway in pig pancreas 35 . In this study, the expression levels of the ER stress markers GRP78 and GRP94 were upregulated by Cd exposure, moreover, the expression levels of IRE1, XBP1, PERK, ATF4, and ATF6 were increased, which established Cd exposure‐induced ER stress in swine myocardium.…”

Section: Discussionmentioning

confidence: 96%

Autophagy flux inhibition mediated by lysosomal dysfunction participates in the cadmium exposure‐induced cardiotoxicity in swine

Zhao

Yao

et al. 2022

BioFactors

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Cadmium (Cd), a common toxic heavy metal, is believed as a risk factor for the induction and progression of cardiovascular disease. Autophagy is a highly ordered intracellular lysosomal-mediated degradation pathway that is crucial for protein and organelle quality control. Autophagy dysfunction could develop exacerbated cardiac dysfunction. However, the role of autophagy in Cd exposure-induced cardiotoxicity remains largely unknown. In this study, the Cd-induced swine cardiotoxicity model was established by feeding with a CdCl 2 suppled diet (20 mg Cd/kg diet). The results showed that Cd exposure increased the expression of endoplasmic reticulum stress-related genes (GRP78, GRP94, IRE1, XBP1, PERK, ATF4, and ATF6), increased the expression of Ca 2+ release channels IP3R and RYR1 and decreased the expression of Ca 2+ uptake pump SERCA1. Cd exposure upregulated the expression of autophagy-related genes (CAMKKII, AMPK, ATG5, ATG7, ATG12, Beclin1, LC3-II, and P62) and downregulated mTOR expression. Cd exposure inhibited the expression of V-ATPase and cathepsins (CTSB and CTSD), and increased the expression of cathepsins in cytoplasm. Cd exposure decreased the colocalization of autophagosome and lysosome. This study revealed that autophagy flux inhibition caused by lysosomal dysfunction participates in the cardiotoxicity induced by Cd exposure in swine.

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Cadmium induces endoplasmic reticulum stress-mediated apoptosis in pig pancreas via the increase of Th1 cells

Cited by 31 publications

References 48 publications

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

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

Cadmium induced mitochondria apoptosis via the reduction of Th2 cells in pig thyroids

Autophagy flux inhibition mediated by lysosomal dysfunction participates in the cadmium exposure‐induced cardiotoxicity in swine

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Cadmium induces endoplasmic reticulum stress-mediated apoptosis in pig pancreas via the increase of Th1 cells

Cited by 31 publications

References 48 publications

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

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

Cadmium induced mitochondria apoptosis via the reduction of Th2 cells in pig thyroids

Autophagy flux inhibition mediated by lysosomal dysfunction participates in the cadmium exposure‐induced cardiotoxicity in swine

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

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