Innate immune and endoplasmic reticulum unfolded protein response pathways protect Caenorhabditis elegans against chloroquine toxicity

Chloroquine (CQ) is a 4-aminoquinoline that has historically been used as an anti-malarial drug. It has also been used to treat several autoimmune diseases, cancers, and viral infections. Most of the effects of CQ are mediated through its ability to accumulate in acidic vacuoles and increase their pH. However, at high doses, CQ is known to have various toxic effects, including ocular, retinal, neuromuscular, renal, and cardiac toxicities. The host responses involved in counteracting CQ toxicity remain poorly characterized. Here, using the Caenorhabditis elegans model, we characterize the host pathways that protect against CQ toxicity. Transcriptomics studies reveal that CQ exposure results in the upregulation of innate immune response and endoplasmic reticulum (ER) unfolded protein response (UPR) pathways. An analysis of multiple immune pathway mutants shows that different immune pathways defend against CQ toxicity. Intriguingly, some of these pathways, which converge to defend against pathogenic bacteria, operate independently to protect against CQ toxicity. Finally, we demonstrate that the ER-UPR pathways also play a crucial role in counteracting CQ toxicity.