Abstract
The use of chemical warfare agents is prohibited but they have been used in recent Middle Eastern conflicts. Their accidental exposure (e.g. arsenical lewisite) is also known and causes extensive painful cutaneous injury. However, their molecular pathogenesis is not understood. Here, we demonstrate that a nexus of stress granules (SGs), integrated stress, and RNA binding proteins (RBPs) Roquin and Reganse-1 play a key role. Lewisite and its prototype phenylarsine oxide (PAO) induce SG assembly in skin keratinocytes soon after exposure, which associate with various RBPs and translation-related proteins. SG disassembly was detected several hours after exposure. The dynamics of SG assembly-disassembly associates with the chemical insult and cell damage. Enhanced Roquin and Regnase-1 expression occurs when Roquin was recruited to SGs and Regnase-1 to the ribosome while in the disassembling SGs their expression is decreased with consequent induction of inflammatory mediators. SG-targeted protein translational control is regulated by the phosphorylation-dependent activation of eukaryotic initiation factors 2α (eIF2α). Treatment with integrated stress response inhibitor (ISRIB), which blocks eIF2α phosphorylation, impacted SG assembly dynamics. Topical application of ISRIB attenuated the inflammation and tissue disruption in PAO-challenged mice. Thus, the dynamic regulation of these pathways provides underpinning to cutaneous injury and identify translational therapeutic approach for these and similar debilitating chemicals.
Highlights
Exposure to arsenical vesicants rapidly causes severe and painful inflammation and blistering responses, primarily in the skin and in other epithelial tissues
We provide further evidence that accumulation of unfolded proteins leads to induction of stress granules (SGs) formation and that the temporal regulation of SG assembly and disassembly correlates with the onset and progression of inflammation and tissue damage caused by arsenical exposure
One of the key events includes the phosphorylation of eukaryotic initiation factors 2a (eIF2a), which in turn reduces the ternary complex, eIF2-GTP-tRNAiMet and that leads to initiation of SG assembly, at least by certain chemicals, as SG formation can occur independent of eIF2a phosphorylation in other models of endoplasmic reticulum (ER) stress such as those induced by sorbitol [20, 33]
Summary
Exposure to arsenical vesicants rapidly causes severe and painful inflammation and blistering responses, primarily in the skin and in other epithelial tissues. Lewisite, was considered to be one of the most toxic and leading candidates for weaponizing arsenicals, as a single agent and as a complex mixture with sulfur mustard, another potent vesicant, for use in World War II [3]. These chemicals were not used due to war accords, and stockpiles were eventually buried at the manufacturing site or sunk in the ocean [4]. 44 victims were poisoned by the mixture of sulfur mustard and lewisite leaking from five drums excavated from an underground parking area in Qiqihar City of Heilongjiang Province, China. In Samukawa, Kanagawa, where the Sagami Naval Arsenal was formerly located, many workers were accidently exposed to lewisite [10]
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