Endoplasmic Reticulum Stress Contributes to Copper-Induced Pyroptosis via Regulating the IRE1α-XBP1 Pathway in Pig Jejunal Epithelial Cells

Copper (Cu) is a common additive in food products, which poses a potential concern to animal and human health when it is in excess. Here, we investigated the relationship between endoplasmic reticulum (ER) stress and pyroptosis in Cu-induced toxicity of jejunum in vivo and in vitro. In in vivo experiments, excess intake of dietary Cu caused ER cavity expansion, elevated fluorescence signals of GRP78 and Caspase-1, and increased the mRNA and protein expression levels related to ER stress and pyroptosis in pig jejunal epithelium. Simultaneously, similar effects were observed in IPEC-J2 cells under excess Cu treatment. Importantly, 4-phenylbutyric acid (ER stress inhibitor) and MKC-3946 (IRE1 alpha inhibitor) significantly inhibited the ER stress-triggered IRE1 alpha-XBP1 pathway, which also alleviated the Cu-induced pyroptosis in IPEC-J2 cells. In general, these results suggested that ER stress participated in regulating Cu-induced pyroptosis in jejunal epithelial cells via the IRE1 alpha-XBP1 pathway, which provided a novel view into the toxicology of Cu.

Automated summary

This study investigated the relationship between endoplasmic reticulum stress and pyroptosis in Copper-induced toxicity of the jejunum. Excess intake of Copper caused expansion of ER cavity and increased expression levels related to ER stress and pyroptosis. Inhibition of ER stress and IRE1 alpha-XBP1 pathway alleviated Copper-induced pyroptosis.