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

Abstract

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 DSSinduced 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 RNAbinding 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.Keywords: arsenite r autophagy r integrated stress response (ISR) pathway r stress granules r TIA-1/TIAR Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…We performed mass spectrometry with M2 TAMs and observed that a cluster of stress-associated proteins were upregulated in MDMs-M2. Many of the differentially expressed proteins ( Figure 2 A) were mainly involved in integrated stress response (ISR), especially SG assembly [ 37 , 38 ]. SG formation was triggered by SG nucleator proteins, such as G3BP1.…”

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“…The formation of stress granules in leukocytes is part of the broader cellular response to inflammatory signals, and it contributes to the regulation of gene expression and the control of immune responses [ 108 ]. For instance, Tia-1 and TIAR-mediated recruitment of IL-1β to SGs suppressed the cytokine expression [ 109 ]. SGs prevent excessive innate immune activation protecting lymphocytes from TNFα/NFκB induced cell death [ 110 ].…”

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“…Likewise, translationally stalled IL-1β mRNAs recruit TIA1 and TIAR, resulting in RBP-RNA SG complexes. The SG pathway regulates IL-1β production, and bound IL-1β mRNAs might undergo degradation through the induction of autophagy [ 108 ]. TIAR is also a component of the RNP in the control of endotoxin-induced macrophage responses [ 109 ].…”