Activation of integrated stress response pathway regulates IL‐1β production through posttranscriptional and translational reprogramming in macrophages

Immune cells sense and programme its cellular machinery appropriately to the environmental changes through the activation of cytoprotective adaptive pathway so‐called the “integrated stress response (ISR)”. However, the mechanisms implicated in ISR‐induced protective responses are poorly understood. Here, we show that ISR activation by arsenite (Ar) results in suppression of IL‐1β production in macrophages and inhibition of DSS‐induced colitis in a murine model through a novel posttranscriptional and translation regulatory (PTR) mechanism. Ar triggers PTR events through eIF2α‐phosphorylation, which results in the attenuation of active polysome formation leading to the accumulation of translationally stalled IL‐1β mRNAs. Translationally stalled IL‐1β mRNAs recruit RNA‐binding proteins (TIA‐1/TIAR), resulting in the formation of RBP‐RNA complexes known as stress granules (SGs). The SGs bound IL‐1β mRNAs might undergo degradation through induction of autophagy. Also, we show that Ar posttranslationally impairs processing and secretion of IL‐1β by diminishing inflammasome activation. Altogether, this study unveils a novel mechanism of IL‐1β regulation and further suggests that pharmacological activation of cytoprotective ISR pathway might provide an effective therapeutic intervention against inflammatory diseases. Activation of integrated stress response (ISR) pathway triggers homeostatic processes and enable cells to adapt to various stress conditions. Here, we have shown that Arsenite mediated ISR activation in macrophages inhibits potent inflammatory cytokine IL‐1β through posttranscriptional and translation regulatory mechanisms and protects mice from chemical‐induced colitis.