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 (IRE1α inhibitor) significantly inhibited the ER stress-triggered IRE1α-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 IRE1α-XBP1 pathway, which provided a novel view into the toxicology of Cu.